[Federal Register Volume 64, Number 123 (Monday, June 28, 1999)]
[Proposed Rules]
[Pages 34608-34625]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-16191]
[[Page 34608]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 5, 206, 250, 314, 600, and 601
[Docket No. 99N-0193]
RIN 0910-AB61
Supplements and Other Changes to an Approved Application
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
its regulations on supplements and other changes to an approved
application to implement the manufacturing changes provision of the
Food and Drug Administration Modernization Act of 1997 (the
Modernization Act). The proposed rule would require manufacturers to
validate the effect of any manufacturing change on the identity,
strength, quality, purity, and potency of a drug or biological product
as those factors relate to the safety or effectiveness of the product.
The proposal sets forth requirements for changes requiring supplement
submission and approval prior to the distribution of the product made
using the change, changes requiring supplement submission at least 30
days prior to the distribution of the product, changes requiring
supplement submission at the time of distribution, and changes to be
described in an annual report.
DATES: Written comments by September 13, 1999. Comments on the
collection of information by July 28, 1999.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852. Submit written comments on the information
collection requirements to the Office of Information and Regulatory
Affairs, Office of Management and Budget (OMB), New Executive Office
Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn: Desk
Officer for FDA.
FOR FURTHER INFORMATION CONTACT:
Eric B. Sheinin, Center for Drug Evaluation and Research (HFD-800),
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857,
301-827-5918, or
Robert A. Yetter, Center for Biologics Evaluation and Research
(HFM-10), Food and Drug Administration, 1401 Rockville Pike, Rockville,
MD 20852, 301-827-0373.
SUPPLEMENTARY INFORMATION:
I. Introduction
On November 21, 1997, the President signed the Modernization Act
(Pub. L. 105-115) into law. Section 116 of the Modernization Act
amended the Federal Food, Drug, and Cosmetic Act (the act) by adding
section 506A (21 U.S.C. 356a), which describes requirements and
procedures for making and reporting manufacturing changes to approved
new drug and abbreviated new drug applications, to new and abbreviated
animal drug applications, and to license applications for biological
products. This proposed rule sets forth regulations to implement
section 506A of the act for human new drug and abbreviated new drug
applications and for licensed biological products. The Center for
Veterinary Medicine is developing separate regulations regarding
manufacturing changes for new and abbreviated animal drug applications.
This proposed rule will update and replace current Sec. 314.70 (21
CFR 314.70), which provides the requirements for manufacturing changes
for human drug applications. This proposal also proposes changes to
Sec. 601.12 (21 CFR 601.12), which provides the requirements for
manufacturing changes for licensed biological products. Although the
current Sec. 601.12 for licensed biological products is in full
compliance with the new provisions in the Modernization Act, FDA is
making the proposed changes in order to maintain harmonization with
proposed Sec. 314.70 for human drug applications.
II. Background
The requirements for reporting manufacturing changes under current
Sec. 314.70 were developed originally as part of a comprehensive effort
to improve the investigational new drug application (IND) and the new
drug application (NDA) processes. This effort began in October 1982 (47
FR 46622, October 19, 1982) and consisted of three phases. The first
phase, termed the NDA rewrite (50 FR 7452, February 22, 1985),
finalized procedures in part 314 (21 CFR part 314), including
Sec. 314.70, for FDA review of new drug and antibiotic applications.
The NDA rewrite of Sec. 314.70 created three mechanisms for reporting
manufacturing changes: Supplements requiring prior approval,
supplements not requiring prior approval, and annual reports. The
rationale behind the need for three mechanisms to report manufacturing
and controls changes is that some changes have a significant potential
to affect the safety or effectiveness of a final drug product and
should be reviewed and approved by FDA prior to distribution of the
product made with the change. Other changes have a lesser potential to
affect safety or effectiveness and could be implemented by a firm with
notification to FDA concurrently (changes being effected supplement). A
third category of changes has a minimal potential to affect safety or
effectiveness and could, therefore, be submitted in the next annual
report without compromising drug safety or effectiveness.
The second phase of the effort to improve the IND and NDA process,
termed the IND rewrite (52 FR 8831, March 19, 1987), finalized FDA
procedures in 21 CFR part 312 for reviewing IND's. The third phase
involved preparation of a series of agency guidances that elaborated on
the concepts contained in the IND and NDA regulations and provided more
detail concerning application formats and how to fulfill testing and
other regulatory requirements.
In implementing Sec. 314.70, the agency recognized both the need
for greater consistency in the approaches FDA recommended for
application holders making postapproval manufacturing and controls
changes as well as a need to reduce regulatory burden consistent with
the public health. Accordingly, FDA formed the Scale-up and
Postapproval Changes (SUPAC) Task Force. This SUPAC Task Force, which
was established by the Center for Drug Evaluation and Research (CDER)
Chemistry, Manufacturing, and Controls Coordinating Committee, oversaw
the acquisition of data on the effects of postapproval changes on the
quality and performance of drugs. Based on the data and CDER's
experience reviewing thousands of manufacturing change supplements,
CDER developed guidance documents designed to ease preapproval
requirements by categorizing certain manufacturing changes according to
whether they had a minor, moderate, or major potential to affect
product quality and performance. The SUPAC guidance documents were
issued under Sec. 314.70(a), which stated that holders of an approved
application shall make changes to the application in accordance with a
guideline, notice, or regulation published in the Federal Register that
provides for a less burdensome notification of the change.
The existing postapproval change guidances are based on the concept
that the identity, strength, quality, purity, and potency of an
approved drug should
[[Page 34609]]
remain unchanged in any important aspect as a result of any
postapproval change in manufacturing and controls. A change in any
important aspect may thus require redemonstration of pharmaceutical
equivalence and/or bioequivalence as defined in 21 CFR 320.1.
Regulations governing manufacturing changes to licensed biological
products were similar to Sec. 314.70, although they did not include the
three categories of changes provided in Sec. 314.70. In 1997, as part
of an agency initiative to reduce regulatory burden, FDA revised
Sec. 601.12 to add three categories of manufacturing changes for
licensed biological products with different reporting requirements for
each category. In addition, because certain biotechnology products were
regulated as drugs under section 505 of the act (21 U.S.C. 355), FDA
sought to harmonize regulatory approaches for those biotechnology
products that were regulated as drugs by adding new Sec. 314.70(g) that
addressed reporting changes to an approved application for certain
biotechnology products (see 61 FR 2739, January 29, 1996, and 62 FR
39890, July 24, 1997). Revised Sec. Sec. 601.12 and 314.70(g), like the
original Sec. 314.70, provided for three risk-based filing categories:
(1) Those having a substantial potential to have an adverse effect on
the identity, strength, quality, purity, and potency of a drug as those
factors relate to the safety or effectiveness of the product; (2) those
having a moderate potential to have these types of effects; and (3)
those with minimal potential to have such effects. In addition,
Sec. Sec. 601.12 and 314.70(g) provided for four different reporting
categories instead of the three originally provided in Sec. 314.70.
These categories were: (1) Prior approval supplement; (2) 30-day wait
changes being effected supplement; (3) no-wait changes being effected
supplement; and (4) annual report.
Sections 601.12 and 314.70(g) also provided that applicants could
submit as a preapproval supplement a comparability protocol that
described the specific tests and validation studies and acceptable
limits to be achieved to demonstrate the lack of adverse effect for
specified types of manufacturing changes on the identity, strength,
quality, purity, or potency of a product as they may relate to the
safety or effectiveness of the product. If approved, such a protocol
could justify a reduced reporting category for the particular change
described because the use of the protocol for the change could reduce
the potential risk of an adverse effect associated with the change.
III. Summary of the Legislation
Section 116 of the Modernization Act amended the act by adding
section 506A, which built upon the concepts embodied in the IND/NDA
rewrite, the SUPAC program, and the changes to Sec. Sec. 601.12 and
314.70(g). Section 506A of the act includes the following provisions:
1. A drug made with a manufacturing change, whether a major
manufacturing change or otherwise, may be distributed only after the
applicant validates the effects of the change on the identity,
strength, quality, purity, and potency of the drug as these factors may
relate to the safety or effectiveness of the drug (sections 506A(a)(1)
and (b) of the act). This section recognizes that additional testing,
beyond testing to ensure that an approved specification is met, is
required to ensure unchanged identity, strength, quality, purity, or
potency as these factors may relate to the safety or effectiveness of
the drug.
2. A drug made with a major manufacturing change may be distributed
only after the applicant submits a supplemental application to FDA and
the supplemental application is approved by the agency. The application
is required to contain information determined to be appropriate by FDA
and include the information developed by the applicant when
``validating the effects of the change'' (section 506A(c)(1) of the
act). The phrase ``validating the effects of the change,'' as used in
this proposed rule, is not the same as ``validation'' required in FDA's
current good manufacturing practice (CGMP) regulations (parts 210 and
211 (21 CFR parts 210 and 211)). Unless otherwise specified by FDA,
some CGMP validation (e.g., process, equipment) data need not be filed
in an NDA, abbreviated new drug application (ANDA), or license
application for a biological product but should be retained at the
facility and be available for review by FDA at its discretion. Some
other CGMP validation information, in addition to the information
validating the effects of the change specified in section 506A(c)(1) of
the act, should be submitted in an NDA, ANDA, or license application
for a biological product (e.g., sterilization and advantageous agent
removal process validation).
3. A major manufacturing change is a manufacturing change
determined by FDA to have substantial potential to adversely affect the
identity, strength, quality, purity, or potency of the drug as these
factors may relate to the safety or effectiveness of the drug. Such
changes include: (1) A change made in the qualitative or quantitative
formulation of the drug involved or in the specifications in the
approved application or license unless exempted by FDA by regulation or
guidance; (2) a change determined by FDA by regulation or guidance to
require completion of an appropriate clinical study demonstrating
equivalence of the drug to the drug manufactured without the change;
and (3) other changes determined by FDA by regulation or guidance to
have a substantial potential to adversely affect the safety or
effectiveness of the drug (section 506A(c)(2) of the act).
4. FDA may require submission of a supplemental application for
drugs made with manufacturing changes that are not major (section
506A(d)(1)(B) of the act) and establish categories of manufacturing
changes for which a supplemental application is required (section
506A(d)(1)(C) of the act). In such a case the applicant may begin
distribution of the drug 30 days after FDA receives a supplemental
application unless the agency notifies the applicant within the 30-day
period that prior approval of the application is required (section
506A(d)(3)(B)(i) of the act). FDA may also designate a category of
manufacturing changes that permit the applicant to begin distributing a
drug made with such changes upon receipt by the agency of a
supplemental application for the change (section 506A(d)(3)(B)(ii) of
the act). If FDA disapproves a supplemental application, the agency may
order the manufacturer to cease the distribution of drugs that have
been made with the disapproved change (section 506A(d)(3)(B)(iii) of
the act).
5. FDA may authorize applicants to distribute drugs without
submitting a supplemental application (section 506A(d)(1)(A) of the
act) and may establish categories of manufacturing changes that may be
made without submitting a supplemental application (section
506A(d)(1)(C) of the act). The applicant is required to submit a report
to FDA on such a change and the report is required to contain
information the agency deems to be appropriate and information
developed by the applicant when validating the effects of the change.
FDA may also specify the date on which the report is to be submitted
(section 506A(d)(2)(A) of the act). If during a single year an
applicant makes more than one manufacturing change subject to an annual
reporting requirement, FDA may authorize the applicant to submit a
single report containing the required information for all the changes
made during the year
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(annual report) (section 506A(d)(2)(B) of the act).
Section 506A of the act provides FDA with considerable flexibility
to determine the information and filing mechanism required for the
agency to assess the effect of manufacturing changes in the safety and
effectiveness of the product. There is a corresponding need to retain
such flexibility in the proposed regulations implementing section 506A
of the act to ensure that the least burdensome means for reporting
changes are available. FDA believes that such flexibility will allow it
to be responsive to increasing knowledge of and experience with certain
types of changes and help ensure the efficacy and safety of the
products involved. For example, a change that may currently be
considered to have a substantial potential to have an adverse effect on
the safety or effectiveness of the product may, at a later date, based
on new information or advances in technology, be determined to have a
lesser potential to have such an adverse effect. Conversely, a change
originally considered to have a minimal or moderate potential to have
an adverse effect on the safety or effectiveness of the product may
later, as a result of new information, be found to have an increased,
substantial potential to adversely affect the product.
The agency believes it can more readily respond to knowledge gained
from manufacturing experience, further research and data collection,
and advances in technology by issuing regulations that set out broad,
general categories of manufacturing changes and by using guidance
documents to provide FDA's current thinking on the specific changes
that fall into those general categories. The proposed rule would,
therefore, help reduce the number of manufacturing changes specifically
identified as requiring supplements.
The agency also understands that applicants expect some
predictability on what type of reporting will be expected for specific
changes. FDA intends to make available guidance documents to describe
the agency's current interpretation of specific changes falling into
the four filing categories and to modify the documents as needed to
reflect changes based on new information. Section 506A of the act
explicitly provides FDA the authority to use guidance documents to
determine the type of changes that do or do not have a substantial
potential to adversely affect the safety or effectiveness of the drug
product. The use of guidance documents will allow FDA to more easily
and quickly modify and update important information. (FDA's use of
guidance documents under current Sec. Sec. 314.70(a) and 601.12 has
proven effective in accomplishing this goal.) Guidance documents will
be developed according to the procedures set out in FDA's ``Good
Guidance Practices'' published in the Federal Register of February 27,
1997 (62 FR 8961 at 8967 through 8972). A notice of availability of a
draft guidance entitled ``Guidance for Industry: Changes to an Approved
NDA or ANDA'' is published elsewhere in this issue of the Federal
Register. This draft guidance covers recommended reporting categories
for various postapproval manufacturing changes. Previously published
guidances, including the SUPAC guidances, provide recommendations on
reporting categories as well as the type of information that should be
developed by the applicant to validate the effect of the change on the
identity, strength, quality, purity, or potency of a product as they
may relate to the safety or effectiveness of the product. To the extent
that the recommendations on reporting categories in this guidance, when
finalized, are inconsistent with previously published guidance, such as
the SUPAC guidances, the recommended reporting categories in such prior
guidance will be superseded by this new guidance upon its publication
in final form. CDER intends to update the previously published
guidances to make them consistent with this guidance.
FDA has also published a guidance entitled ``Changes to an Approved
Application for Specified Biotechnology and Specified Synthetic
Biological Products'' (62 FR 39904, July 24, 1997). FDA intends to
update this guidance as appropriate based on any final rule that may
issue as a result of this proposal.
IV. Description of the Proposed Rule
A. Definitions
FDA is proposing to amend the ``Definitions'' sections of the
regulations on applications for FDA approval to market a new drug
(Sec. 314.3) and a biological product (21 CFR 600.3) by adding
definitions for ``specification'' and ``validate the effects of the
change.'' These definitions are necessary to implement the provisions
of section 506A of the act.
FDA is proposing to define ``specification'' as the quality
standard (i.e., tests, analytical procedures, and acceptance criteria)
provided in an approved application to confirm the quality of drug
substances, drug products, intermediates, raw materials, reagents, and
other components including container closure systems, and in-process
materials. FDA is proposing to define ``specification'' because under
section 506A of the act a ``major change'' includes a change ``in the
specifications in the approved application or license.''
To clarify the meaning of the term ``acceptance criteria'' as used
in the definition of ``specification,'' FDA is including in the
proposed definition of ``specification'' the statement that
``acceptance criteria'' refers to numerical limits, ranges, or other
criteria for the tests described. To determine if a material being
tested complies with a specification, there must be predetermined
criteria. These criteria may include numerical limits or ranges (e.g.,
not more than 1 percent) or other criteria (e.g., white to off-white in
color).
FDA is proposing to define ``validate the effects of the change''
as an assessment of the effect of a manufacturing change on the
identity, strength, quality, purity, or potency of a drug as these
factors relate to the safety or effectiveness of the drug. FDA is
proposing to define this phrase because section 506A of the act
includes a requirement that a drug made with a manufacturing change may
only be distributed after the applicant ``validates the effects of the
change.'' Validating the effects of the change is important in
determining whether manufacturing changes alter the identity, strength,
quality, purity, or potency of a drug product as they relate to drug
safety or effectiveness, and may require testing beyond that in an
approved specification, such as testing to ensure pharmaceutical
equivalence and/or bioequivalence.
B. Changes to an Approved Application
Current Sec. 314.70(a) sets forth general requirements under which
an applicant must notify FDA when making a change to an approved
application. This section states that an applicant must notify FDA
about each change in each condition established in an approved
application beyond the variations already provided for in the
application, and that the notice is required to describe the change
fully. It also states that, depending on the type of change, the
applicant must notify FDA of it in a supplement under current
Sec. 314.70(b) or (c) or by inclusion of the information in an annual
report under current Sec. 314.70(d). FDA is proposing to retain these
general requirements under proposed Sec. 314.70(a)(1). A similar
provision is included in the regulations on changes to an approved
application for biological products under current Sec. 601.12(a). FDA
is proposing to
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redesignate this requirement as Sec. 601.12(a)(1).
Proposed Sec. 314.70(a)(2) would require the holder of an approved
application under section 505 of the act to validate the effects of
manufacturing changes on the identity, strength (e.g., assay and
content uniformity), quality (e.g., physical, chemical, and biological
properties), purity (e.g., impurities and degradation products) or
potency (e.g., biological activity, bioavailability, and
bioequivalence) of a drug as these factors may relate to the safety and
effectiveness of the drug. These validation requirements must be met
before a product made with a manufacturing change may be distributed.
This amendment implements section 506A(a)(1) and (b) of the act. A
similar provision is included in the regulations on changes to an
approved application for biological products under current
Sec. 601.12(a). FDA is proposing to add minor wording changes for
consistency with revised Sec. 314.70 and to redesignate this
requirement as Sec. 601.12(a)(2). In addition, applicants continue to
be subject to the validation requirements of parts 210 and 211 as
mentioned previously.
Current Sec. 314.70(a) states that notwithstanding the supplement
submission requirements of current Sec. 314.70(b) and (c), an applicant
shall make a manufacturing change in accordance with ``a guideline,
notice, or regulation published in the Federal Register that provides
for a less burdensome notification of the change.'' For example, a type
of manufacturing change subject to prior approval by FDA under current
Sec. 314.70(b) might be identified in a ``guideline, notice, or
regulation'' as a change that could be reported in a supplement not
requiring prior approval or in an annual report. In the SUPAC guidance
documents, CDER used this provision to reduce the regulatory burden for
submission of supplements for manufacturing changes that were not
likely to adversely affect drug product quality or performance.
FDA is proposing to retain this requirement under proposed
Sec. 314.70(a)(3) and to add it to the regulations on changes to an
approved application for biological products as proposed
Sec. 601.12(a)(3). This exception may be used as pharmaceutical science
evolves for those changes that FDA no longer considers to have a
substantial potential to have an adverse effect on the product.
However, to ensure consistency with the principles of FDA's good
guidance practices, proposed Sec. Sec. 314.70(a)(3) and 601.12(a)(3)
would eliminate the reference to a Federal Register ``notice'' and
change the word ``guideline'' to ``guidance.'' Proposed
Sec. 314.70(a)(3) is expressly sanctioned in section 506A(c)(2)(A),
(c)(2)(B), and (c)(2)(C) of the act which permit FDA to categorize
manufacturing changes ``by regulation or guidance.''
Current Sec. 314.70(c) states, in the introductory paragraph, that
the applicant who submits a change being effected supplement to FDA
must promptly revise all promotional labeling and drug advertising to
make it consistent with any change in the labeling. FDA is proposing to
retain this provision as proposed Sec. 314.70(a)(4) and to add it to
the regulations on changes to an approved application for biological
products as proposed Sec. 601.12(a)(4). Because the prompt revision of
all promotional labeling and product advertising applies equally to all
labeling changes (see Sec. 314.81(b)(3)), FDA is proposing that this
provision expressly apply to labeling changes requiring approval prior
to the distribution of the product, labeling changes that may be
submitted in a changes being effected supplement, and those changes
that may be filed in an annual report.
Current Sec. 314.70(a) also requires that, except for a
supplemental application providing for a change in the labeling, the
applicant, other than a foreign applicant, shall include in each
supplemental application providing for a change under paragraph (b) or
(c) of current Sec. 314.70, a statement certifying that a field copy of
the supplement has been provided to the applicant's home FDA district
office. FDA is proposing to retain this requirement as proposed
Sec. 314.70(a)(5). However, as proposed, this section would omit the
phrase ``other than a foreign applicant'' because foreign applicants
now routinely supply field copies of supplements to the agency.
Proposed Sec. Sec. 314.70(a)(6) and 601.12(a)(5) would add a
requirement that a list of all changes contained in the supplement or
annual report must be included in the cover letter for the supplement
or annual report. For many years, most supplements and annual reports
have routinely included such cover letters. Including a list of all
changes in the cover letters will enable FDA to more efficiently locate
and evaluate changes in what are often substantial documents, thus
facilitating FDA review of supplements and annual reports.
C. Changes Requiring Supplement Submission and Approval Prior to
Distribution of the Product Made Using the Change (Major Changes)
Certain drug or biological product manufacturing steps are so
critical that changes in these steps must be submitted in a supplement
to FDA and approved by FDA prior to distribution of the product made
using the change. Similarly, certain labeling changes must be approved
prior to distribution of the product with the new labeling. Current
regulations at Sec. Sec. 314.70(b) and (g)(1) and 601.12(b) set forth
prior approval requirements. FDA is proposing to revise these
regulations to implement section 506A of the act. Proposed
Sec. 314.70(b)(1) would implement section 506A(c)(1) and (c)(2) of the
act and would require that a preapproval supplement must be submitted
for any change in the product, production process, quality controls,
equipment, or facilities that has a substantial potential to have an
adverse effect on the identity, strength, quality, purity, or potency
of the product as these factors may relate to the safety or
effectiveness of the product.
Sometimes, during assessment of a change, an applicant will find
that the manufacturing change will have an adverse effect on the
identity, strength, quality, purity, or potency of the drug product. In
many cases, the applicant will not implement this manufacturing change,
but in some cases may still wish to do so. If an assessment concludes
that a manufacturing change has adversely affected the identity,
strength, quality, purity, or potency of the drug product, the change
should be filed in a prior approval supplement, regardless of whether
the change is one that normally does not need FDA approval prior to
distribution of the product made with the change. The applicant could
submit this change in a prior approval supplement with appropriate
information to support the continued safety and effectiveness of the
product. The agency will assess the effect of any adverse change in a
drug product, as the change may relate to the safety or effectiveness
of the product, during the review of the prior approval supplement.
Proposed Sec. 314.70(b)(4) would retain the provision in current
Sec. 314.70(b) that provides that an applicant may request an expedited
review of a supplement if a delay in making the change would impose an
extraordinary hardship. Proposed Sec. 314.70(b)(4) would also permit a
request for an expedited review of a supplement for public health
reasons. FDA is retaining the provision
[[Page 34612]]
for expedited review for extraordinary hardship reasons but wishes to
clarify that these requests should be reserved for manufacturing
changes made necessary by catastrophic events (e.g., fire) or by events
that could not be reasonably foreseen and for which the applicant could
not plan. FDA is also proposing to add this provision for expedited
review, as proposed in Sec. 314.70(b)(4), to the regulations on changes
to an approved application for biological products as proposed
Sec. 601.12(b)(4). Requests for expedited review will be assessed on a
case-by-case basis. All requests may not be granted.
Proposed Sec. 314.70(b)(2) lists changes requiring supplement
submission and FDA approval prior to distribution, including changes
designated as major manufacturing changes in section 506A(c)(2) of the
act and changes to certain biotechnology products that are currently
subject to prior approval requirements under current Sec. 314.70(g)(1).
These changes have a substantial potential to have an adverse effect on
the identity, strength, quality, purity, or potency of the product as
these factors may relate to the safety or effectiveness of the product.
The agency believes that the filing mechanism for these significant
changes is unlikely to vary with technological advances or due to
differences among products, and that these changes should be enumerated
in the proposed regulations. The agency's continued prior review and
approval of such changes is necessary to protect the public from
products for which safety or effectiveness may have been compromised.
The changes in proposed Sec. 314.70(b)(2) would include but are not
limited to the following changes.
1. Changes in the qualitative or quantitative formulation of the
drug, including inactive ingredients, or in the specifications in the
approved application or license, except as provided in proposed
Sec. 314.70(c) and (d) (proposed Sec. 314.70(b)(2)(i)). Section
506A(c)(2)(A) of the act specifically requires that this change be
submitted in a supplement requiring FDA approval prior to distribution.
These types of changes are included under current Sec. 314.70(b) and
(g) as requiring a prior approval supplement. FDA is also proposing to
revise current Sec. 601.12(b)(2)(i) in the regulations on changes to an
approved application for biological products to be consistent with
proposed Sec. 314.70(b)(2)(i).
2. Changes requiring completion of studies in accordance with part
320 (21 CFR part 320) to demonstrate the equivalence of the drug to the
drug as manufactured without the change or to the reference listed drug
(proposed Sec. 314.70(b)(2)(ii)). A similar change is included under
current Sec. 314.70(g)(1) as requiring a prior approval supplement. FDA
is proposing that these changes be submitted in a supplement requiring
prior approval because section 506A of the act provides that a major
manufacturing change shall include a change ``determined by the
Secretary by regulation or guidance to require completion of an
appropriate clinical study demonstrating equivalence of the drug to the
drug as manufactured without the change''(section 506A(c)(2)(B) of the
act). The studies most likely to be conducted to support a
manufacturing change would be bioavailability or bioequivalence studies
conducted in humans in accordance with FDA regulations at part 320.
Well-controlled clinical trials or nonclinical tests may also be used
to establish bioavailability or bioequivalence (Sec. 320.24). These are
the types of studies the statute refers to as demonstrating the
equivalence of one drug to another. FDA proposes interpreting
``Appropriate clinical stud[ies],'' referenced in section 506A(c)(2)(B)
of the act for NDA products, to be ``studies in accordance with part
320 of this chapter'' to clarify the types of studies triggering a
prior approval supplement. This phrase is used in the proposed
regulation at Sec. 314.70(b)(2)(ii).
Section 506A of the act also states in part that ``equivalence of
the drug to the drug as manufactured without the change'' should be
demonstrated. FDA is including in proposed Sec. 314.70(b)(2)(ii) the
statement that the equivalence of the drug may sometimes be
demonstrated by comparison to a reference listed drug. This is
consistent with the drug approval requirements for generic drugs
because, at the time of approval, a generic drug applicant is required
to show equivalence between the proposed generic drug and a reference
listed drug, and a proposed manufacturing change should not
significantly change the equivalence demonstrated at the time of
approval (Sec. 320.21(b)). For the more significant manufacturing
changes for generic drugs, the applicant is required to conduct a
bioequivalence study comparing the drug product made with the change to
the reference listed drug. FDA is not proposing the same changes to
Sec. 601.12 because biological products are not subject to part 320 and
have unique properties. Therefore, the agency will retain the wording
in current Sec. 601.12(b)(2)(ii).
3. Changes that may affect product sterility assurance, such as
changes in product or component sterilization method(s) or an addition,
deletion, or substitution of steps in an aseptic processing operation
(proposed Sec. 314.70(b)(2)(iii)). Current Sec. Sec. 314.70(g)(1) and
601.12(b)(2)(vi) require a prior approval supplement for this change.
4. Changes in the synthesis or manufacture of the drug substance
that may affect the impurity profile and/or the physical, chemical, or
biological properties of the drug substance (proposed
Sec. 314.70(b)(2)(iv)). A similar change in current Sec. 314.70(b)(1)
requires a prior approval supplement.
5. Changes in labeling, except those described in proposed
Sec. 314.70(c)(6)(iii) (changes to add or strengthen certain warnings
or statements), Sec. 314.70(d)(2)(ix) (certain changes in the
description or information about a drug), and Sec. 314.70(d)(2)(x)
(certain editorial or minor changes) (proposed Sec. 314.70(b)(2)(v)).
This change requires a prior approval supplement under current
Sec. 314.70(b)(3).
6. Changes in a container closure system that controls drug
delivery or that may affect the impurity profile of the drug product
(proposed Sec. 314.70(b)(2)(vi)). Significant changes in container
closure systems require a prior approval supplement under current
Sec. 314.70(b)(2).
7. Changes solely affecting a natural product, a recombinant
deoxyribonucleic acid (DNA)-derived protein/polypeptide product, or a
complex or conjugate of a drug with a monoclonal antibody for: (1)
Changes in the virus or adventitious agent removal or inactivation
method(s); (2) changes in the source material or cell line; and (3)
establishment of a new master cell bank or seed (proposed
Sec. 314.70(b)(2)(vii)). This change requires a prior approval
supplement under current Sec. 314.70(g)(1).
8. Changes to a product under an application subject to a validity
assessment because of significant questions regarding the integrity of
the data supporting that application (proposed
Sec. 314.70(b)(2)(viii)). Until questions about the integrity of the
data in the application have been resolved, there are inadequate
assurances that any change will not adversely affect the safety or
effectiveness of the product. Moreover, a change to a product cannot be
validated, as required under 506A(b) of the act, until the integrity of
the underlying data in such application is validated. Consequently,
there is a significant potential that the change will have an adverse
effect on the identity, strength, quality, purity, or potency of the
product. After a validity assessment has been completed, and data
integrity
[[Page 34613]]
questions resolved, the holder of an approved application may submit
supplements for manufacturing changes as otherwise provided in
Sec. 314.70.
FDA is proposing to describe additional specific examples of
changes that have substantial, moderate, and minimal potential to
adversely affect a product in guidance documents rather than enumerate
them in this proposed regulation. As discussed previously, section 116
of the Modernization Act expressly states that the agency may through
guidance categorize the manufacturing changes. FDA anticipates that
scientific advances and future experience may reduce the need for
premarket approval of certain changes, and the agency will respond to
changed circumstances by revising the guidance documents. A notice of
availability of a draft guidance document entitled ``Guidance for
Industry: Changes to an Approved NDA or ANDA'' that provides more
detailed recommendations on how to report proposed changes is being
published elsewhere in this issue of the Federal Register, and the
agency is soliciting comments on the guidance as well as on the
proposed rule.
Current Sec. 314.70(b)(1) requires that supplements requiring prior
approval be submitted for the following changes in a drug substance:
(1) Relaxing the limits for a specification (Sec. 314.70(b)(1)(i)); (2)
establishing a new regulatory analytical method
(Sec. 314.70(b)(1)(ii)); (3) deleting a specification or regulatory
analytical method (Sec. 314.70(b)(1)(iii)); (4) changing the synthesis
of the drug substance, including a change in solvents and a change in
the route of synthesis (Sec. 314.70(b)(1)(iv)); and (5) using a
different facility or establishment to manufacture the drug substance
(Sec. 314.70(b)(1)(v)). FDA is proposing to revoke current
Sec. 314.70(b)(1)(i), (b)(1)(ii), and (b)(1)(iii) because these relate
to a change in a specification which is already covered under proposed
Sec. 314.70(b)(1). FDA is proposing to revoke current
Sec. 314.70(b)(1)(iv) and (b)(1)(v) because some of these changes would
fall into the proposed major manufacturing change category while others
would fall into other proposed categories depending on whether the
change is considered to have a substantial, moderate, or minimal
potential to adversely affect the identity, strength, quality, purity,
or potency of the drug as they may relate to the safety or
effectiveness of the drug. FDA has decided not to include these changes
in this proposed rule, but plans to provide recommendations on the
filing mechanisms for these types of changes in the guidance documents
discussed previously.
Current Sec. 314.70(b)(2) requires that supplements requiring prior
approval be submitted for the following changes in a drug product: (1)
Adding or deleting an ingredient, or otherwise changing the composition
of the drug product, other than deletion of an ingredient intended only
to affect the color of the drug product (Sec. 314.70(b)(2)(i)); (2)
relaxing the limits for a specification (Sec. 314.70(b)(2)(ii)); (3)
establishing a new regulatory analytical method
(Sec. 314.70(b)(2)(iii)); (4) deleting a specification or regulatory
analytical method (Sec. 314.70(b)(2)(iv)); (5) changing the method of
manufacture of the drug product, including changing or relaxing an in-
process control (Sec. 314.70(b)(2)(v)); (6) using a different facility
or establishment, including a different contract laboratory or labeler,
to manufacture, process, or pack the drug product
(Sec. 314.70(b)(2)(vi)); (7) changing the container and closure system
for the drug product or changing a specification or regulatory
analytical method for the container and closure system
(Sec. 314.70(b)(2)(vii)); (8) changing the size of the container,
except for solid dosage forms, without a change in the container and
closure system (Sec. 314.70(b)(2)(viii)); (9) extending the expiration
date of the drug product based on data obtained under a new or revised
stability testing protocol that has not been approved in the
application (Sec. 314.70(b)(2)(ix)); (10) establishing a new procedure
for reprocessing a batch of the drug product that fails to meet
specifications (Sec. 314.70(b)(2)(x)); (11) adding a code imprint by
printing with ink on a solid oral dosage form drug product
(Sec. 314.70(b)(2)(xi)); (12) adding a code imprint by embossing,
debossing, or engraving on a modified release solid oral dosage form
drug product (Sec. 314.70(b)(2)(xii)). FDA is proposing to revoke
Sec. 314.70(b)(2)(i) through (b)(2)(iv) because these provisions relate
to a change in qualitative or quantitative formulation or a
specification that is already covered under proposed Sec. 314.70(b)(1).
FDA is proposing to revoke current Sec. 314.70(b)(2)(v) through
(b)(2)(xii) because some changes would fall into the proposed major
manufacturing changes category while others would fall into other
proposed categories. FDA plans to provide recommendations on the filing
mechanism for these changes in the guidance documents discussed
previously.
Proposed Sec. 314.70(b)(3) states that the applicant must obtain
approval of a supplement from FDA before distributing a product using a
change under Sec. 314.70(b), and specifies information to be included
in the supplement. The supplement must include: (1) A detailed
description of the proposed change; (2) the product(s) involved; (3)
the manufacturing site(s) or area(s) affected; (4) a description of the
methods used and studies performed to evaluate the effect of the change
on the identity, strength, quality, purity, or potency of the product
as these factors may relate to the safety or effectiveness of the
product (validating the effects of the change); (5) data derived from
such studies; (6) for a natural product, a recombinant DNA-derived
protein/polypeptide product, or a complex or conjugate of a drug with a
monoclonal antibody, relevant validation protocols must be provided in
addition to the requirements under Sec. 314.70(b)(3)(iv) and (b)(3)(v);
(7) for sterilization process and test methodologies, relevant
validation protocols must be provided in addition to the requirements
under Sec. 314.70(b)(3)(iv) and (b)(3)(v); and (8) if applicable, a
reference list of relevant standard operating procedures (SOP's). These
supplement content requirements are already required under current
Sec. Sec. 314.70(g)(1)(iii) and 601.12(b)(3), and FDA is proposing to
retain the requirements in this rule, except that the proposal
specifies that relevant validation protocols and data apply to a
natural product, a recombinant DNA-derived protein/polypeptide product,
or a complex or conjugate of a drug with a monoclonal antibody, as well
as protocols and data for sterilization processes and test
methodologies.
Current Sec. 314.70(g)(1)(iii) only applies to recombinant DNA-
derived protein/polypeptide products or complexes or conjugates of a
drug with a monoclonal antibody. Some information requirements listed
under current Sec. 314.70(g)(1)(iii) are not applicable to all CDER
drug products. FDA is proposing to clarify the requirements in current
Sec. 314.70(g)(1)(iii) to describe the limited circumstances under
which certain information would be required.
D. Changes Requiring Supplement Submission at Least 30 Days Prior to
Distribution of the Drug Product Made Using the Change (Moderate
Changes)
Current Sec. 314.70(c) describes changes that may be made before
FDA approval of a supplement. These include changes to enhance the safe
use of a drug by adding specifications to strengthen warnings, or to
delete false, misleading, or unsupported indications for use. Current
Sec. 314.70(g)(2) describes changes requiring supplement submission at
least 30 days prior to distribution of the
[[Page 34614]]
product made using the change. These include changes in the site of
testing from one facility to another, an increase or decrease in
production scale during finishing steps that involves new or different
equipment, and replacement of equipment with that of similar, but not
identical, design and operating principle that does not affect the
process methodology or process operating parameters. FDA recognizes
that the public health can be adequately protected without requiring
approval of certain manufacturing changes prior to distribution of the
product made with the change. FDA continues to believe that it is
important that such changes be documented and validated so there is a
mechanism for assessing the consequences of the change and that the
agency approve such changes. Ready access to information regarding such
changes through submission of a supplement 30 days before distribution
of the product would protect against the distribution of unsafe or
ineffective products while speeding the availability of improved
products.
Proposed Sec. 314.70(c) implements section 506A(d)(1)(B) and
(d)(3)(B)(i) of the act and provides that products made using changes
listed under this section may be distributed not sooner than 30 days
after receipt of a supplement by FDA. Proposed Sec. 314.70(c)(1) would
require that a supplement be submitted for any change in the product,
production process, quality controls, equipment, or facilities that has
a moderate potential to have an adverse effect on the identity,
strength, quality, purity, or potency of the product as these factors
may relate to the safety or effectiveness of the product. Proposed
Sec. 314.70(c)(3) states that a supplement submitted under paragraph
(c)(1) is required to give a full explanation of the basis for the
change and identify the date on which the change is to be made, and
that the supplement must be labeled ``Supplement--Changes Being
Effected in 30 Days'' or, if applicable under paragraph (c)(6) of this
section, ``Supplement--Changes Being Effected.''
Proposed Sec. 314.70(c)(2) describes the types of changes that
would be included under this section:
1. A change in the container closure system that does not affect
the quality of the final drug product (proposed Sec. 314.70(c)(2)(i)).
2. Changes solely affecting a natural protein product, a
recombinant DNA-derived protein/polypeptide product or a complex or
conjugate of a drug with a monoclonal antibody, including: (1) An
increase or decrease in production scale during finishing steps that
involves new or different equipment and (2) replacement of equipment
with that of similar, but not identical, design and operating principle
that does not affect the process methodology or process operating
parameters (proposed Sec. 314.70(c)(2)(ii)). These changes are listed
in current Sec. 314.70(g)(2) as requiring the submission of a
supplement at least 30 days prior to distribution.
Current Sec. 314.70(g)(2) lists a change in the site of testing
from one facility to another as a change that must be filed in a
supplement submitted at least 30 days prior to distribution. FDA has
decided not to include a similar change in proposed Sec. 314.70(c) and
is proposing to delete this change from current Sec. 601.12(c)(2)(i).
FDA plans to provide recommendations on the filing mechanism for this
change in the guidance documents discussed previously.
Proposed Sec. 314.70(c)(4) states that distribution of a product
made using a change under this section may begin not less than 30 days
after receipt of a supplement by FDA. This section would also require
that the same information listed in paragraph (b)(3), discussed
previously, must be contained in the supplement required under proposed
Sec. 314.70(c).
Proposed Sec. 314.70(c)(5) states that during the 30-day period
following receipt of the supplement, FDA would perform a preliminary
review to determine whether the supplement is complete and whether the
type of change is appropriate for review as a supplement under proposed
Sec. 314.70(c). If the proposed change is determined to be a major
change that should be submitted under proposed Sec. 314.70(b), the
agency would inform the applicant and the applicant would be required
to receive FDA approval before a product produced with the change could
be distributed. If FDA determines that the change is properly submitted
as a supplement under Sec. 314.70(c), but the required information is
incomplete, the applicant would be required to supply the missing
information and wait until FDA has determined that the supplement is in
compliance before distributing the product. These provisions are
provided in section 506A(d)(3) of the act. These requirements are
included under current Sec. Sec. 314.70(g)(2)(iv) and 601.12(c)(4) and
FDA is retaining and expanding this requirement to cover all drugs.
Under proposed Sec. 314.70(c)(7), if FDA disapproves a supplemental
application under this section, the agency may order the manufacturer
to cease distribution of the drug products made with the manufacturing
change. This amendment would implement section 506A(d)(3)(B)(iii) of
the act. FDA is also proposing to add this provision to the regulations
on changes to an approved application for biological products as
proposed Sec. 601.12(c)(6).
E. Changes That May Be Implemented When FDA Receives a Supplement
(Moderate Changes)
Under proposed Sec. 314.70(c)(6), FDA may designate a category of
changes for which the holder of an approved application making such a
change may begin distribution of the drug upon receipt by FDA of a
supplemental application for the change. This provision implements
section 506A(d)(3)(B)(ii) of the act. FDA recognizes that the public
health can be adequately protected without requiring approval of
certain manufacturing changes prior to distribution of the product made
with the change. FDA continues to believe that it is important that
such changes be documented and validated so there is a mechanism for
assessing the consequences of the changes and for the agency to approve
such changes. However, based on FDA's experience, certain changes may
be implemented when FDA receives the supplement, rather than delaying
distribution for 30 days. In general, these changes provide the same or
increased assurance that the product will have the characteristics of
identity, strength, quality, purity, or potency that it purports or is
represented to have. Ready access to information by FDA regarding such
changes, through the submission of a supplement, would protect against
the distribution of unsafe or ineffective products while speeding the
availability of improved products.
These changes include, but are not limited to:
1. The addition to a specification or changes in the methods or
controls to provide increased assurance that the drug will have the
characteristics of identity, strength, quality, purity, or potency that
it purports or is represented to possess (proposed
Sec. 314.70(c)(6)(i)). A similar change is listed under current
Sec. 314.70(c). Proposed Sec. 314.70(c)(6)(i) revises current
Sec. 314.70(c) to provide clarification based on the proposed
definition of specification and to delete the reference to facilities.
FDA plans to provide recommendations on the filing mechanism for
facility changes in the guidance documents discussed previously.
2. A change in the size and/or shape of a container (containing the
same
[[Page 34615]]
labeled amount of product) for a nonsterile drug product, except for
solid dosage forms, without a change from one container closure system
to another (proposed Sec. 314.70(c)(6)(ii)). A similar change is listed
under current Sec. 314.70(b) as requiring prior approval. The proposal
differs from the existing rule in that it only applies to nonsterile
drug products, thereby reducing the potential risks and eliminating the
need for a prior approval requirement. FDA is also clarifying that
changes in container size relate to changes in the physical size of the
container and do not include changes in the labeled amount of the drug.
3. Changes in the labeling to add or strengthen a contraindication,
warning, precaution, or adverse reaction, or to add or strengthen a
statement about drug abuse, dependence, psychological effect, or
overdosage, or to add or strengthen an instruction about dosage and
administration that is intended to increase the safe use of the product
(proposed Sec. 314.70(c)(6)(iii)(A), (c)(6)(iii)(B), and
(c)(6)(iii)(C)). These changes are required under current
Sec. 314.70(c)(2), except that FDA is proposing to include labeling
changes relating to adding or strengthening a statement about
psychological effects to maintain consistency with current
Sec. 601.12(f)(2)(B).
4. The deletion of false, misleading, or unsupported indications
for use or claims for effectiveness (proposed
Sec. 314.70(c)(6)(iii)(D)). This change is required under current
Sec. 314.70(c)(2).
5. Any other labeling changes specifically requested by FDA
(proposed Sec. 314.70(c)(6)(iii)(E)). FDA is proposing to include this
change under this section to enable the agency to allow for labeling
changes that normally require prior approval to be submitted in a
changes being effected supplement when FDA specifically requests the
change. FDA is also proposing to add this requirement to the
regulations on changes to an approved application for biological
products as proposed Sec. 601.12(f)(2)(i)(E).
Current Sec. 314.70(c)(3) lists the following changes to use a
different facility or establishment to manufacture the drug substance
that may be made before FDA approval: (1) Where the manufacturing
process in the new facility or establishment does not differ materially
from that in the former facility or establishment, and (2) where the
new facility or establishment has received a satisfactory CGMP
inspection within the previous 2 years covering that manufacturing
process. FDA is proposing not to include these changes in this proposed
rule but plans to provide recommendations on the filing mechanism for
these changes in the guidance documents discussed previously.
F. Changes To Be Described in the Next Annual Report (Minor Changes)
Proposed Sec. 314.70(d) would provide that changes to the product,
production process, quality controls, equipment, or facilities that
have a minimal potential to have an adverse effect on the identity,
strength, quality, purity, or potency of the product as these factors
may relate to the safety or effectiveness of the product would be
documented by the applicant in the next annual report in accordance
with current Sec. 314.81(b)(2). This provision is provided in section
506A(d)(2) of the act. FDA recognizes that there are manufacturing
changes that have minimal potential to have an adverse effect on a
product's safety or effectiveness. FDA believes that prior agency
approval of these changes is unnecessary and is proposing in
Sec. 314.70(d) that such changes would not be required to be approved
by the agency. FDA continues to believe that it is important that such
changes be documented and validated so there is a mechanism for
assessing the consequences of the change. FDA can effectively assess
compliance with Sec. 314.70(d) and CGMP requirements for changes that
have a minimal potential to adversely affect the product's safety or
effectiveness by having ready access to information regarding such
changes through submission of an annual report and by inspection.
Under proposed Sec. 314.70(d)(2), these changes would include, but
are not limited to:
1. Any change made to comply with an official compendium that is
consistent with FDA requirements and provides increased assurance that
the drug will have the characteristics of identity, strength, quality,
purity, or potency that it purports or is represented to possess
(proposed Sec. 314.70(d)(2)(i)). Similar changes are listed in current
Sec. 314.70(d) and (g) as changes to be described in the next annual
report. FDA is limiting the situations in which these changes can be
submitted in an annual report because certain changes in a
specification (e.g., deleting a test, relaxing acceptance criteria) are
not considered to have minimal potential to effect a product's safety
or effectiveness. FDA is also proposing to revise current
Sec. 601.12(d)(2)(i) in the regulations on changes to an approved
application for biological products to be consistent with proposed
Sec. 314.70(d)(2)(i).
2. The deletion or reduction of an ingredient intended only to
affect the color of the product (proposed Sec. 314.70(d)(2)(ii)). A
similar change is listed in current Sec. 314.70(d) and (g)(3) which
states that the deletion of an ingredient intended only to affect the
color of the drug product should be submitted in an annual report. FDA
is proposing to broaden this provision to include changes that reduce
the quantity of an ingredient intended only to affect the color of the
product. FDA is also proposing to revise current Sec. 601.12(d)(2)(ii)
in the regulations on changes to an approved application for biological
products to be consistent with proposed Sec. 314.70(d)(2)(ii).
3. The replacement of equipment with that of the same design and
operating principles except for equipment used with a natural protein
product, a recombinant DNA-derived protein/polypeptide product, or a
complex or conjugate of a drug with a monoclonal antibody (proposed
Sec. 314.70(d)(2)(iii)). FDA is proposing to add this change to clarify
when certain changes in equipment could be reported in an annual
report. In general, under current regulations (e.g.,
Sec. 314.70(b)(2)(v)), changes in process, which may include changes in
equipment, require a prior approval supplement and this proposal would
reduce the regulatory burden without adversely affecting the quality of
the drug product.
4. A change in the size and/or shape of a container containing the
same number of dose units for a nonsterile solid dosage form, without a
change from one container closure system to another (proposed
Sec. 314.70(d)(2)(iv)). A similar change is listed in current
Sec. 314.70(d) and (g)(3) which states that a change in the size of a
container for a solid dosage form without a change from one container
and closure system to another must be filed in an annual report. FDA is
proposing to broaden this provision to include a change in the shape of
the container. FDA is also clarifying that a change in container size
relates to a change in the physical size of the container and does not
include a change involving the number of dosage units. FDA is also
proposing to revise current Sec. 601.12(d)(2)(v) in the regulations on
changes to an approved application for biological products to be
consistent with proposed Sec. 314.70(d)(2)(iv).
5. A change within the container closure system for a nonsterile
drug product, based upon a showing of equivalency to the approved
system under a protocol approved in the application or published in an
official
[[Page 34616]]
compendium (proposed Sec. 314.70(d)(2)(v)). A similar change is listed
in current Sec. 314.70(d) and (g)(3) which states that a change within
the container and closure system for the drug product (for example, a
change from one high density polyethylene (HDPE) to another HDPE),
except a change in container size for nonsolid dosage forms, based upon
a showing of equivalency to the approved system under a protocol
approved in the application or published in an official compendium,
should be submitted in an annual report. The current regulations limit
this provision by excluding a change in container size for nonsolid
dosage forms. FDA is proposing to broaden this provision to allow such
changes for all nonsterile drug products. FDA is also proposing to
revise current Sec. 601.12(d)(2)(iv) in the regulations on changes to
an approved application for biological products to be consistent with
proposed Sec. 314.70(d)(2)(v).
6. An extension of an expiration dating period based upon full
shelf life data on full production batches obtained from a protocol
approved in the application (proposed Sec. 314.70(d)(2)(vi)). A similar
change is listed under current Sec. 314.70(d) and (g)(3) as one to be
filed in an annual report. FDA is clarifying that the extension of an
expiration date in an annual report should be based on data from full
production batches. FDA is also proposing to revise current
Sec. 601.12(d)(2)(iii) regarding changes to an approved application for
biological products to be consistent with proposed
Sec. 314.70(d)(2)(vi).
7. The addition, deletion, or revision of an alternate analytical
procedure that provides the same or increased assurance of the
identity, strength, quality, purity, or potency of the material being
tested as the analytical procedure described in the approved
application (proposed Sec. 314.70(d)(2)(vii)). A similar change is
listed in current Sec. 314.70(d) and (g)(3) which state that the
addition or deletion of an alternate analytical method should be filed
in an annual report. FDA is proposing to broaden this provision to
include revisions of alternate analytical procedures. FDA is also
clarifying that any changes in alternate analytical procedures should
provide the same or increased assurance of the identity, strength,
quality, purity, or potency of the material being tested as the
analytical procedure described in the approved application. FDA is also
proposing to revise current Sec. 601.12(d)(2)(vii) in the regulations
on changes to an approved application for biological products to be
consistent with proposed Sec. 314.70(d)(2)(vii).
8. The addition by embossing, debossing, or engraving of a code
imprint to a solid oral dosage form drug product other than a modified
release dosage form, or a minor change in an existing code imprint
(proposed Sec. 314.70(d)(2)(viii)). These changes are listed in current
Sec. 314.70(d) and (g)(3) as changes to be described in the next annual
report.
9. A change in the labeling concerning the description of the drug
product or in the information about how the drug is supplied, that does
not involve a change in the dosage strength or dosage form (proposed
Sec. 314.70(d)(2)(ix)). These changes are listed in current
Sec. 314.70(d) as changes to be described in the next annual report.
10. An editorial or similar minor change in labeling (proposed
Sec. 314.70(d)(2)(x)). These changes are listed in current
Sec. 314.70(d) as changes to be described in the next annual report.
Under proposed Sec. 314.70(d)(3), an applicant must submit in the
annual report a list of all products involved and: (1) A statement by
the holder of the approved application that the effects of the change
have been validated; (2) a full description of the manufacturing and
controls changes, including the manufacturing site(s) or area(s)
involved; and (3) the date each change was made, a cross-reference to
relevant validation protocol(s) and/or SOP's, and relevant data from
studies and tests performed to evaluate the effect of the change on the
identity, strength, quality, purity, or potency of the product as these
factors may relate to the safety or effectiveness of the product
(validating the effects of the change). FDA is also proposing to revise
current Sec. 601.12(d)(3) in the regulations on changes to an approved
application for biological products to add, as proposed
Sec. 601.12(d)(3)(iii), the requirement that the applicant must submit
a statement that the effects of the change have been validated.
G. Other Information
Under proposed Sec. 314.70(e), an applicant may submit one or more
protocols describing specific tests, validation studies, and acceptable
limits to be achieved to demonstrate the lack of an adverse effect for
specified types of manufacturing changes on the identity, strength,
quality, purity, or potency of the drug as these factors may relate to
the safety or effectiveness of the drug. Such protocols, or changes to
a protocol, would be submitted as a supplement requiring prior approval
from FDA prior to distribution of the drug. If the supplement is
approved, the use of such a protocol in making the specified changes
may justify a reduced reporting category for the change because of the
reduced risk of an adverse effect. This proposed requirement is
provided for in current Sec. Sec. 314.70(g)(4) and 601.12(e).
Generally, when considering a change in the manufacture of a
product, the manufacturer will prepare a protocol, often called a
``comparability protocol,'' identifying tests to be performed in
evaluating the change and its effect on the product and defining the
criteria against which the impact of the change will be evaluated. By
providing FDA an opportunity to review and approve the comparability
protocol before it is used by the applicant to evaluate a change, FDA
can have greater assurance that the change is being properly evaluated
and there is, therefore, less potential for the change to have an
adverse effect on the safety or effectiveness of the product.
Under proposed Sec. 314.70(f), an applicant would be required to
comply with the patent information requirements under section 505(c)(2)
of the act. This proposed requirement is identical to the current
requirement at Sec. 314.70(e).
Proposed Sec. 314.70(g) would require an applicant claiming
exclusivity under Sec. 314.108 to include, with the supplemental
application, information required under Sec. 314.50(j). This proposed
requirement is identical to the current requirement at Sec. 314.70(f).
In addition to section 506A of the act, other sections of the act
authorize FDA to revise Sec. Sec. 314.70 and 601.12. Sections 301 and
501 of the act (21 U.S.C. 331 and 351) prohibit the manufacture,
processing, packing, or holding of drugs that do not conform to CGMP;
the use of unsafe color additives in or on a drug under section 721 of
the act (21 U.S.C. 379e); and the distribution of a drug that differs
in the strength, purity, or quality that it purports or is represented
to possess. Sections 301 and 502 of the act (21 U.S.C. 352) prohibit
false or misleading labeling of drugs, including, under section 201(n)
of the act (21 U.S.C. 321(n)), failure to reveal material facts
relating to potential consequences under customary conditions of use;
drugs that lack adequate directions for use and adequate warnings; and
the distribution of drugs that are dangerous to health when used in the
manner suggested in their labeling. Under section 505 of the act, FDA
will approve an NDA if the drug is shown to be safe and effective for
its intended use and if, among other things, the methods used
[[Page 34617]]
in, and the facilities and controls used for, the manufacture,
processing and packing of the drug are adequate to preserve its
identity, strength, quality, and purity. Section 701 of the act (21
U.S.C. 371) authorizes FDA to issue regulations for the efficient
enforcement of the act.
The Public Health Service Act (the PHS Act) provides additional
authority for FDA to revise Sec. 601.12. Section 351(a) of the PHS Act
(42 U.S.C. 262(a)) provides that license applications for biological
products may be approved upon a showing that the product is safe, pure,
and potent and that the manufacturing facility meets standards designed
to ensure continued safety, purity, and potency of the product. In
addition, under section 351(b) of the PHS Act, biological products and
their containers or packages may not be falsely labeled or marked.
V. Conforming Amendments
The regulations on supplements and changes to an approved
application or license are cited throughout FDA's regulations. Because
FDA is proposing to revise these regulations, the agency is taking this
opportunity to make conforming amendments to 21 CFR parts 5, 206, 250,
314, 600, and 601 to reflect these proposed regulations. These
conforming amendments will ensure the accuracy and consistency of the
regulations.
VI. Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the
Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Order
12866 directs agencies to assess all costs and benefits of available
regulatory alternatives and, when regulation is necessary, to select
regulatory approaches that maximize net benefits (including potential
economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). Executive Order 12866
classifies a rule as significant if it meets any one of a number of
specified conditions, including having an annual effect on the economy
of $100 million or adversely affecting in a material way a sector of
the economy, competition, or jobs. Under the Regulatory Flexibility
Act, if a rule has a significant economic impact on a substantial
number of small entities, an agency must analyze regulatory options
that would minimize any significant impact of the rule on small
entities. Title II of the Unfunded Mandates Reform Act (in section 202)
requires that agencies prepare a written assessment of anticipated
costs and benefits before proposing any rule that may result in an
expenditure in any one year by State, local, and tribal governments, in
the aggregate, or by the private sector of $100 million (adjusted
annually for inflation).
The agency believes that this proposed rule is consistent with the
regulatory philosophy and principles identified in Executive Order
12866 and in these two statutes. As shown in the following paragraphs,
the rule will not be significant as defined by the Executive Order and
the Unfunded Mandates Reform Act, and the agency certifies that the
proposed rule will not have a significant economic impact on a
substantial number of small entities.
The purpose of the proposed rule is to implement section 506A of
the act and to reduce the number of manufacturing changes subject to
supplements requiring FDA approval prior to product distribution. The
proposed rule would affect all drug manufacturers that submit
manufacturing supplements and would result in a substantial reduction
in burdens to applicants making manufacturing changes subject to the
proposed regulation. The proposed rule would permit earlier
implementation of the changes and quicker marketing of products
improved by manufacturing or labeling modifications. Faster
implementation can result in marked gains in production efficiency, and
generally reduces the paperwork burden associated with reporting the
changes to the agency. For example, a report by the Eastern Research
Group (ERG), an FDA contractor, on the effects of the SUPAC guidance
for immediate release solid oral dosage forms (SUPAC-IR) found that
reducing the number of changes that require preapproval gives companies
greater control over their production resources, which could lead to
significant net savings to industry (Eastern Research Group,
Pharmaceutical Industry Cost Savings Through Use of the Scale-Up and
Post-Approval Guidance for Immediate Release Solid Oral Dosage Forms
(SUPAC-IR), January 7, 1998, Contract No. 223-94-8301). Such economic
incentives may encourage manufacturers to improve their products,
product labeling, and methods of manufacture.
Due to the multiplicity of products and manufacturing changes, the
agency has not estimated the total savings to industry as a result of
this rule, but anticipates that they would increase over time. New
information and technology will allow a greater number of changes to be
reported in supplements that do not require prior approval or in annual
reports. ERG estimated that companies may already have saved $71
million in 1997 due to the agency's implementation of more flexible
reporting procedures for chemistry, manufacturing, and control changes.
This proposed rule would broaden the potential scope of such savings.
Because the proposal would benefit manufacturers regardless of size and
impose no additional costs, the agency certifies that this rule will
not have a significant adverse economic impact on a substantial number
of small entities.
VII. Paperwork Reduction Act of 1995
This proposed rule contains collections of information that are
subject to review by OMB under the Paperwork Reduction Act of 1995 (the
PRA) (44 U.S.C. 3501-3520). ``Collection of information'' includes any
request or requirement that persons obtain, maintain, retain, or report
information to the agency, or disclose information to a third party or
to the public (44 U.S.C. 3502(3) and 5 CFR 1320.3(c)). The title,
description, and respondent description of the information collection
are shown under this section VII with an estimate of the annual
reporting burden. Included in the estimate is the time for reviewing
instructions, gathering and maintaining the data needed, and completing
and reviewing the collection of information.
FDA invites comments on: (1) Whether the proposed collection of
information is necessary for proper performance of FDA's functions,
including whether the information will have practical utility; (2) the
accuracy of FDA's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information on respondents, including through the use of
automated collection techniques, when appropriate, and other forms of
information technology.
Title: Supplements and Other Changes to an Approved Application.
Description: The proposed rule would implement the manufacturing
changes provision of section 116 of the Modernization Act and require
manufacturers to validate the effect of any manufacturing change on the
identity, strength, quality, purity, and potency of a drug or
biological product as those factors relate to the safety or
effectiveness of the product. The respondent would report the change to
[[Page 34618]]
FDA in one of the following ways depending on the potential for the
change to have an adverse effect on the safety or effectiveness of the
product: (1) Changes that have a substantial potential to have an
adverse effect on a product would be submitted in a supplement
requiring prior approval by FDA before distribution of the product made
using the change; (2) changes that have a moderate potential to have an
adverse effect on a product would be submitted to FDA in a supplement
not less than 30 days prior to distribution of the product made using
the change; (3) changes that have a moderate potential to have an
adverse effect on a product would be submitted to FDA in a supplement
at the time of distribution of the product made using the change ; and
(4) changes that have a minimal potential to have an adverse effect on
a product would be documented by the respondent in the next annual
report.
Proposed Sec. Sec. 314.70(a)(2) and 601.12(a)(2) would require the
holder of an approved application to validate the effects of a
manufacturing change on the identity, strength, quality, purity, or
potency of the drug as these factors may relate to the safety or
effectiveness of the drug before distributing a drug made with the
change. This proposed requirement implements the statutory requirement
for information collection under section 506A(a) and (b) of the act
and, therefore, no burden estimate has been calculated for this
regulation.
Proposed Sec. Sec. 314.70(a)(4) and 601.12(a)(4) would require the
applicant to promptly revise all promotional labeling and advertising
to make it consistent with any labeling change implemented. The
transmittal to FDA of advertisements and promotional labeling for drugs
and biologics is accompanied by Form FDA 2253 and regulated by
Sec. Sec. 314.81(b)(3)(i) and 601.12(f)(4). This information collection
is approved by OMB until August 31, 2001, under OMB control number
0910-0376. Therefore, this requirement is not estimated in Table 1 of
this document.
Proposed Sec. 314.70(a)(5) would require that the applicant include
in each supplement (except for a supplement providing for a change in
the labeling) a statement certifying that a field copy of the
supplement has been provided to the applicant's home FDA district
office. Based on data concerning the number of supplements received by
the agency, FDA estimates that approximately 4,278 certifications and
field copies will be submitted annually as required by proposed
Sec. 314.70(a)(5). FDA estimates that approximately 594 applicants will
submit these certifications and field copies. Preparation of a field
copy would involve copying material already prepared for the
supplement, and FDA estimates that it will take an average of 1 hour
for applicants to include an additional field copy for FDA.
Proposed Sec. Sec. 314.70(a)(6) and 601.12(a)(5) would require the
applicant to include in the cover letter a list of all changes
contained in the supplement or annual report. Based on data concerning
the number of supplements and annual reports received by the agency,
FDA estimates that approximately 11,913 lists of all changes in the
supplement or annual report will be submitted annually as required by
proposed Sec. 314.70(a)(6). FDA estimates that approximately 704
applicants will submit these lists. Because the information required
would be generated in preparing the supplement or annual report, the
agency estimates that, under proposed Sec. 314.70(a)(6), it will take
approximately 1 hour to include a list of changes in a cover letter for
a supplement or an annual report. FDA estimates that approximately
2,983 lists of all changes in the supplement or annual report will be
submitted annually as required by proposed Sec. 601.12(a)(5). FDA
estimates that approximately 190 applicants will submit these lists.
Because the information required would be generated in preparing the
supplement or annual report, the agency estimates that, under proposed
Sec. 601.12(a)(5), it will take approximately 1 hour to include a list
of changes in a cover letter for a supplement or an annual report.
Proposed Sec. 314.70(b) and current Sec. 601.12(b) set forth
requirements for changes requiring supplement submission and approval
prior to distribution of the product made using the change (major
changes). Proposed Sec. 314.70(b)(1) and current Sec. 601.12(b)(1)
state that a supplement must be submitted for any change in the
product, production process, quality controls, equipment, or facilities
that has a substantial potential to have an adverse effect on the
identity, strength, quality, purity, or potency of the product as these
factors may relate to the safety or effectiveness of the product.
Under proposed Sec. 314.70(b)(3) and current Sec. 601.12(b)(3), the
applicant must obtain approval of a supplement from FDA prior to
distribution of a product made using the change, and the following must
be contained in the supplement: (i) A detailed description of the
proposed change; (ii) The product(s) involved; (iii) The manufacturing
site(s) or area(s) affected; (iv) A description of the methods used and
studies performed to evaluate the effect of the change on the identity,
strength, quality, purity, or potency of the product as these factors
may relate to the safety or effectiveness of the product (validating
the effects of the change); (v) The data derived from such studies;
(vi) For a natural product, a recombinant DNA-derived protein/
polypeptide product, or a complex or conjugate of a drug with a
monoclonal antibody, relevant validation protocols must be provided;
(vii) For sterilization process and test methodologies, relevant
validation protocols must be provided; and (viii) A reference list of
relevant standard operating procedures when applicable.
The changes requiring supplement submission and approval prior to
distribution of the product made using the change (major changes) are
listed in proposed Sec. 314.70(b)(2) and current Sec. 601.12(b)(2)
(including proposed Sec. 601.12(b)(2)(i)): (i) Changes in the
qualitative or quantitative formulation of the drug, including inactive
ingredients, or in the specifications provided in the approved
application; (ii) Changes requiring completion of studies in accordance
with 21 CFR part 320 to demonstrate the equivalence of the drug to the
drug as manufactured without the change or to the reference listed
drug; (iii) Changes that may affect product sterility assurance, such
as changes in product or component sterilization method(s) or an
addition, deletion, or substitution of steps in an aseptic processing
operation; (iv) Changes in the synthesis or manufacture of the drug
substance that may affect the impurity profile and/or the physical,
chemical, or biological properties of the drug substance; (v) Certain
changes in labeling; (vi) Changes in a container closure system that
controls drug delivery or that may affect the impurity profile of the
drug product; (vii) Changes solely affecting a natural product, a
recombinant DNA-derived protein/polypeptide product, or a complex or
conjugate of a drug with a monoclonal antibody for the following: (A)
Changes in the virus or adventitious agent removal or inactivation
method(s); (B) Changes in the source material or cell line; and (C)
Establishment of a new master cell bank or seed; (viii) Changes to a
product under an application that is subject to a validity assessment
because of significant questions regarding the integrity of the data
supporting that application.
Under proposed Sec. Sec. 314.70(b)(4) and 601.12(b)(4), an
applicant may ask FDA to expedite its review of a supplement for public
health reasons or if a delay in making the change described in it would
impose an extraordinary
[[Page 34619]]
hardship on the applicant. Such a supplement and its mailing cover
should be marked: ``Prior Approval Supplement-Expedited Review
Requested.''
Based on data concerning the number of supplements received by the
agency, FDA estimates that approximately 1,744 supplements will be
submitted annually under proposed Sec. 314.70(b)(1) and (b)(3). FDA
estimates that approximately 594 applicants will submit such
supplements, and that it will take approximately 80 hours to prepare
and submit to FDA each supplement. FDA estimates that approximately 903
supplements are submitted annually under Sec. 601.12(b)(1) and (b)(3).
FDA estimates that approximately 190 applicants submit such
supplements, and that it takes approximately 80 hours to prepare and
submit to FDA each supplement. The burden for an applicant's request,
under proposed Sec. Sec. 314.70(b)(4) and 601.12(b)(4), for FDA to
expedite its review of a supplement is negligible and has not been
estimated in Table 1 of this document.
Proposed Sec. 314.70(c) and current Sec. 601.12(c) set forth
requirements for changes requiring supplement submission at least 30
days prior to distribution of the product made using the change
(moderate changes). Proposed Sec. 314.70(c)(1) and current
Sec. 601.12(c)(1) state that a supplement must be submitted for any
change in the product, production process, quality controls, equipment,
or facilities that has a moderate potential to have an adverse effect
on the identity, strength, quality, purity, or potency of the product
as these factors may relate to the safety or effectiveness of the
product. Under proposed Sec. 314.70(c)(1), the applicant must submit 12
copies of final printed labeling for all labeling changes.
Under proposed Sec. 314.70(c)(3) and current Sec. 601.12(c)(1), the
supplement must set forth a full explanation of the basis for the
change and identify the date on which the change is to be made. The
supplement must be labeled ``Supplement--Changes Being Effected in 30
Days.'' Under proposed Sec. 314.70(c)(4) and current Sec. 601.12(c)(3),
distribution of the product made using the change may begin not less
than 30 days after receipt of the supplement by FDA. The information
listed previously for proposed Sec. 314.70(b)(3) and current
Sec. 601.12(b)(3) must be contained in the supplement.
The changes requiring supplement submission at least 30 days prior
to distribution of the product made using the change (moderate changes)
are listed in proposed Sec. 314.70(c)(2) (the changes in
Sec. 314.70(c)(2)(ii)(A) and (c)(2)(ii)(B) are also listed in current
Sec. 601.12(c)(2)): (i) A change in the container closure system that
does not affect the quality of the final drug product; and (ii) Changes
solely affecting a natural protein product, a recombinant DNA-derived
protein/polypeptide product or a complex or conjugate of a drug with a
monoclonal antibody, including: (A) An increase or decrease in
production scale during finishing steps that involves new or different
equipment; and (B) Replacement of equipment with that of similar, but
not identical, design and operating principle that does not affect the
process methodology or process operating parameters.
Based on data concerning the number of supplements received by the
agency, FDA estimates that approximately 2,754 supplements will be
submitted annually under proposed Sec. 314.70(c)(1), (c)(3), and
(c)(4). FDA estimates that approximately 594 applicants will submit
such supplements, and that it will take approximately 50 hours to
prepare and submit to FDA each supplement. FDA estimates that
approximately 255 supplements are submitted annually under
Sec. 601.12(c)(1) and (c)(3). FDA estimates that approximately 98
applicants submit such supplements, and that it takes approximately 50
hours to prepare and submit to FDA each supplement.
Under proposed Sec. 314.70(c)(6) and current Sec. 601.12(c)(5), FDA
may designate a category of changes for the purpose of providing that,
in the case of a change in such category, the holder of an approved
application may commence distribution of the drug upon receipt by the
agency of a supplement for the change. These changes include: (i)
Addition to a specification or changes in the methods or controls to
provide increased assurance that the drug will have the characteristics
of identity, strength, quality, purity, or potency that it purports or
is represented to possess; (ii) A change in the size and/or shape of a
container for a nonsterile drug product, except for solid dosage forms,
without a change in the labeled amount of product or from one container
closure system to another; (iii) Changes in the labeling to accomplish
any of the following: (A) To add or strengthen a contraindication,
warning, precaution, or adverse reaction; (B) To add or strengthen a
statement about drug abuse, dependence, psychological effect, or
overdosage; (C) To add or strengthen an instruction about dosage and
administration that is intended to increase the safe use of the
product; (D) To delete false, misleading, or unsupported indications
for use or claims for effectiveness; or (E) Any other changes
specifically requested by FDA. Under proposed Sec. 314.70(c)(3) and
current Sec. 601.12(c)(1), the supplement must be labeled
``Supplement--Changes Being Effected.''
Based on data concerning the number of supplements received by the
agency, FDA estimates that approximately 486 supplements will be
submitted annually under proposed Sec. 314.70(c)(6). FDA estimates that
approximately 486 applicants will submit such supplements, and that it
will take approximately 50 hours to prepare and submit to FDA each
supplement. FDA estimates that approximately 47 supplements are
submitted annually under Sec. 601.12(c)(5). FDA estimates that
approximately 34 applicants submit such supplements, and that it takes
approximately 50 hours to prepare and submit to FDA each supplement.
Proposed Sec. 314.70(d) and current Sec. 601.12(d) set forth
requirements for changes to be described in an annual report (minor
changes). Proposed Sec. 314.70(d)(1) and current Sec. 601.12(d)(1)
state that changes in the product, production process, quality
controls, equipment, or facilities that have a minimal potential to
have an adverse effect on the identity, strength, quality, purity, or
potency of the product as these factors may relate to the safety or
effectiveness of the product must be documented by the applicant in the
next annual report.
Under proposed Sec. 314.70(d)(3) and current Sec. 601.12(d)(3)
(including proposed Sec. 601.12(d)(3)(iii)), the applicant must submit
in the annual report a list of all products involved; and (i) A
statement by the holder of the approved application that the effects of
the change have been validated; (ii) A full description of the
manufacturing and controls changes, including the manufacturing site(s)
or area(s) involved; and (iii) The date each change was made, a cross-
reference to relevant validation protocols and/or SOP's, and relevant
data from studies and tests performed to evaluate the effect of the
change on the identity, strength, quality, purity, or potency of the
product as these factors may relate to the safety or effectiveness of
the product (validation).
The changes to be described in an annual report (minor changes)
are listed in proposed Sec. 314.70(d)(2) and current Sec. 601.12(d)(2)
(including proposed Sec. 601.12(d)(2)(i) through (d)(2)(v) and
(d)(2)(vii)): (i) Any change made to comply with an official compendium
that is consistent with FDA requirements and provides increased
assurance that the drug will have the
[[Page 34620]]
characteristics of identity, strength, quality, purity, or potency that
it purports or is represented to possess; (ii) The deletion or
reduction of an ingredient intended to affect only the color of the
product; (iii) Replacement of equipment with that of the same design
and operating principles except for equipment used with a natural
protein product, a recombinant DNA-derived protein/polypeptide product,
or a complex or conjugate of a drug with a monoclonal antibody; (iv) A
change in the size and/or shape of a container containing the same
number of dosage units for a nonsterile solid dosage form, without a
change from one container closure system to another; (v) A change
within the container closure system for a nonsterile drug product,
based upon a showing of equivalency to the approved system under a
protocol approved in the application or published in an official
compendium; (vi) An extension of an expiration dating period based upon
full shelf-life data obtained from a protocol approved in the
application; (vii) The addition, deletion, or revision of an alternate
analytical procedure that provides the same or increased assurance of
the identity, strength, quality, purity, or potency of the material
being tested as the analytical procedure described in the approved
application; (viii) The addition by embossing, debossing, or engraving
of a code imprint to a solid oral dosage form drug product other than a
modified release dosage form, or a minor change in an existing code
imprint; (ix) A change in the labeling concerning the description of
the drug product or in the information about how the drug is supplied,
that does not involve a change in the dosage strength or dosage form;
and (x) An editorial or similar minor change in labeling.
Based on data concerning the number of supplements and annual
reports received by the agency, FDA estimates that approximately 6,929
annual reports will include documentation of certain manufacturing
changes as required under proposed Sec. 314.70(d)(1) and (d)(3). FDA
estimates that approximately 704 applicants will submit such
information, and that it will take approximately 10 hours to prepare
and submit to FDA the information for each annual report. FDA estimates
that approximately 227 annual reports include documentation of certain
manufacturing changes as required under current Sec. 601.12(d)(1) and
(d)(3). FDA estimates that approximately 166 applicants submit such
information, and that it takes approximately 10 hours to prepare and
submit to FDA the information for each annual report. Proposed
Sec. 314.70(d)(3) and current Sec. 601.12(d)(3) require a statement by
the applicant that the effects of the change have been validated. This
information is developed by the applicant to validate the effects of
the change regarding identity, strength, quality, purity, and potency,
and is expressly required to be submitted under section 506A(d)(3)(A)
of the act. Therefore, the burden associated with such collection of
information is not included in the estimates of Table 1 of this
document.
The proposed regulation would reduce the overall number of
manufacturing changes subject to supplements, particularly those
requiring FDA approval prior to product distribution. Many changes that
are currently reported in supplements would be reported in annual
reports. Supplement submissions contain more burdensome reporting
requirements than a submission through an annual report. The proposed
regulation would not increase the number of annual reports but would
allow applicants to include in an annual report information currently
required to be reported to the agency in a supplemental application.
The number of manufacturing changes currently reported in supplements
that would be reported in annual reports is approximately 1,283.
Proposed Sec. 314.70(e) and current Sec. 601.12(e) state that an
applicant may submit one or more protocols describing the specific
tests and validation studies and acceptable limits to be achieved to
demonstrate the lack of adverse effect for specified types of
manufacturing changes on the identity, strength, quality, purity, or
potency of the drug as these factors may relate to the safety or
effectiveness of the drug. Any such protocols, or changes to a
protocol, must be submitted as a supplement requiring approval from FDA
prior to distribution of a drug produced with the manufacturing change.
The supplement, if approved, may subsequently justify a reduced
reporting category for the particular change because the use of the
protocol for that type of change reduces the potential risk of an
adverse effect.
Based on data concerning the number of supplements received by the
agency, FDA estimates that approximately 50 protocols will be submitted
annually under proposed Sec. 314.70(e). FDA estimates that
approximately 50 applicants will submit such protocols, and that it
will take approximately 20 hours to prepare and submit to FDA each
protocol. FDA estimates that approximately 20 protocols are submitted
annually under Sec. 601.12(e). FDA estimates that approximately 14
applicants submit such protocols, and that it takes approximately 20
hours to prepare and submit to FDA each protocol.
Current Sec. 601.12(f) sets forth the requirements for supplement
submission for labeling changes for biological products. Current
Sec. 601.12(f)(2)(i)(A) through (f)(2)(i)(D) specify those labeling
changes for which an applicant must submit a supplement to FDA at the
time the change is made. Proposed Sec. 601.12(f)(2)(i)(E) would add
``any other changes specifically requested by FDA'' to these types of
changes. FDA estimates that approximately 12 labeling supplements are
submitted annually under current Sec. 601.12(f)(1). FDA estimates that
approximately 12 applicants submit these supplements, and that it takes
approximately 40 hours to prepare and submit to FDA each supplement.
FDA estimates that approximately 10 labeling supplements are submitted
annually under current Sec. 601.12(f)(2), including those that would be
submitted under proposed Sec. 601.12(f)(2)(i)(E). FDA estimates that
approximately 10 applicants submit these supplements, and that it takes
approximately 20 hours to prepare and submit to FDA each supplement.
FDA estimates that approximately 100 annual reports for labeling
changes are submitted under current Sec. 601.12(f)(3). FDA estimates
that approximately 70 applicants submit these reports, and that it
takes approximately 10 hours to prepare and submit to FDA each report.
FDA estimates that approximately 1,495 labeling supplements are
submitted annually under current Sec. 601.12(f)(4). FDA estimates that
approximately 61 applicants submit these supplements, and that it takes
approximately 10 hours to prepare and submit to FDA each supplement.
Proposed Sec. 314.70(f) states that an applicant must comply with
the patent information requirements under section 505(c)(2) of the act.
Proposed Sec. 314.70(g) states that an applicant must include any
applicable exclusivity information with a supplement as required under
Sec. 314.50(j). Patent and exclusivity information collection
requirements are approved by OMB until May 31, 2001, under OMB control
number 0910-0305. Therefore, this requirement is not estimated in Table
1 of this document.
Description of Respondents: Business or other for-profit
organizations.
In compliance with section 3507(d) of the PRA (44 U.S.C. 3507(d)),
the agency has submitted a copy of this proposed rule to OMB for its
review and approval of these information collections.
[[Page 34621]]
Interested persons are requested to send comments regarding this
collection of information, including suggestions for reducing this
burden, to the Office of Information and Regulatory Affairs, OMB
(address above), Attn: Wendy Taylor, Desk Officer for FDA. Submit
written comments on the collection of information by July 28, 1999.
Table 1.--Estimated Annual Reporting Burden1
----------------------------------------------------------------------------------------------------------------
No. of
21 CFR Section No. of Responses per Total Annual Hours per Total Hours
Respondents Respondent Responses Response
----------------------------------------------------------------------------------------------------------------
314.70(a)(5) 594 7 4,278 1 4,278
314.70(a)(6) 704 17 11,913 1 11,913
314.70(b)(1) and (b)(3) 594 3 1,744 80 139,520
314.70(c)(1),(c)(3), and 594 5 2,754 50 137,700
(c)(4)
314.70(c)(6) 486 1 486 50 24,300
314.70(d)(1) and (d)(3) 704 10 6,929 10 69,290
314.70(e) 50 1 50 20 1,000
601.12(a)(5) 190 16 2,983 1 2,983
601.12(b)(1) and (b)(3) 190 5 903 80 72,240
601.12(c)(1) and (c)(3) 98 3 255 50 12,750
601.12(c)(5) 34 1 47 50 2,350
601.12(d)(1) and (d)(3)6 1 227 10 2,270
601.12(e) 14 1 20 20 400
601.12(f)(1) 12 1 12 40 480
601.12(f)(2) 10 1 10 20 200
601.12(f)(3) 70 1 100 10 1,000
601.12(f)(4) 61 25 1,495 10 14,950
Total 497,624
----------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.
VIII. Environmental Impact
The agency has determined under 21 CFR 25.30(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
IX. Request for Comments
Interested persons may, on or before September 13, 1999, submit to
the Dockets Management Branch (address above) written comments
regarding this proposal. Two copies of any comments are to be
submitted, except that individuals may submit one copy. Comments are to
be identified with the docket number found in brackets in the heading
of this document. Received comments may be seen in the office above
between 9 a.m. and 4 p.m., Monday through Friday. Submit written
comments on the information collection requirements as described in
paragraph VII of this document by July 28, 1999.
List of Subjects
21 CFR Part 5
Authority delegations (Government agencies), Imports, Organization
and functions (Government agencies).
21 CFR Parts 206 and 250
Drugs.
21 CFR Part 314
Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.
21 CFR Part 600
Biologics, Reporting and recordkeeping requirements.
21 CFR Part 601
Administrative practice and procedure, Biologics, Confidential
business information.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR parts 5, 206, 250, 314, 600, and 601 be amended as
follows:
PART 5--DELEGATIONS OF AUTHORITY AND ORGANIZATION
1. The authority citation for 21 CFR part 5 continues to read as
follows:
Authority: 5 U.S.C. 504, 552, App. 2; 7 U.S.C. 138a, 2271; 15
U.S.C. 638, 1261-1282, 3701-3711a; 15 U.S.C. 1451-1461; 21 U.S.C.
41-50, 61-63, 141-149, 321-394, 467f, 679(b), 801-886, 1031-1309; 35
U.S.C. 156; 42 U.S.C. 241, 242, 242a, 242l, 242n, 243, 262, 263,
264, 265, 300u-300u-5, 300aa-1; 1395y, 3246b, 4332, 4831(a), 10007-
10008, E.O. 11921, 41 FR 24294, 3 CFR, 1977 Comp., p. 124-131; E.O.
12591, 52 FR 13414, 3 CFR, 1988 Comp., p. 220-223.
Sec. 5.80 [Amended]
2. Section 5.80 Approval of new drug applications and their
supplements is amended in the first sentence of paragraphs (d) and (f)
by removing the phrase ``Sec. Sec. 314.70(b)(1), (b)(2)(ii) through
(b)(2)(x), (c)(1), and (c)(3)'' and by adding in its place the phrase
``Sec. 314.70(b)(1), (b)(2)(i) excluding changes in qualitative or
quantitative formulation, (b)(2)(iii), (b)(2)(iv), (b)(2)(vi),
(b)(2)(vii), (c)(2)(i), (c)(2)(ii), (c)(6)(i), and (c)(6)(ii)''; and in
the first sentence of paragraph (e) by removing the phrase
``Sec. Sec. 314.70(b)(3) and (c)(2)(i) through (c)(2)(iv)'' and by
adding in its place the phrase ``Sec. 314.70(b)(2)(v) and
(c)(6)(iii)''.
PART 206--IMPRINTING OF SOLID ORAL DOSAGE FORM DRUG PRODUCTS FOR
HUMAN USE
3. The authority citation for 21 CFR part 206 is revised to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 355, 371; 42 U.S.C.
262.
Sec. 206.10 [Amended]
4. Section 206.10 Code imprint required is amended in the first
sentence of paragraph (b) by removing the phrase
``Sec. 314.70(b)(2)(xi) or (b)(2)(xii)'' and by adding in its place the
phrase ``Sec. 314.70(b)''.
PART 250--SPECIAL REQUIREMENTS FOR SPECIFIC HUMAN DRUGS
5. The authority citation for 21 CFR part 250 continues to read as
follows:
Authority: 21 U.S.C. 321, 336, 342, 352, 353, 355, 361(a),
362(a) and (c), 371, 375(b).
[[Page 34622]]
Sec. 250.250 [Amended]
6. Section 250.250 Hexachlorophene, as a component of drug and
cosmetic products is amended in the last sentence of paragraph
(c)(4)(ii) by removing the phrase ``Sec. 314.70(c)(2)'' and by adding
in its place the phrase ``Sec. 314.70(c)(6)(iii)''.
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG
7. The authority citation for 21 CFR part 314 is revised to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356a, 371,
374, 379e.
8. Section 314.3 is amended in paragraph (b) by alphabetically
adding the definitions for ``Specification'' and ``Validate the effects
of the change'' to read as follows:
Sec. 314.3 Definitions.
* * * * *
(b) * * *
Specification means the quality standard (i.e., tests, analytical
procedures, and acceptance criteria) provided in an approved
application to confirm the quality of drug substances, drug products,
intermediates, raw materials, reagents, and other components including
container closure systems, and in-process materials. For the purpose of
this definition, acceptance criteria means numerical limits, ranges, or
other criteria for the tests described.
* * * * *
Validate the effects of the change means to assess the effect of a
manufacturing change on the identity, strength, quality, purity, or
potency of a drug as these factors relate to the safety or
effectiveness of the drug.
9. Section 314.50 is amended in paragraph (d)(1)(ii)(b) by removing
the phrase ``specifications and test procedures'' and by adding in its
place the word ``specification''; in paragraph (d)(1)(v) by removing
the phrase ``Except for a foreign applicant, the'' and by adding in its
place the word ``The''; in paragraph (d)(3)(i) by adding the word
``procedures'' after the word ``analytical''; in paragraph (d)(3)(ii)
by removing the phrases ``specifications or analytical methods'' and
``specification or analytical methods'' each time they appear and by
adding in their places the phrase ``tests, analytical procedures, and
acceptance criteria''; in paragraph (d)(4)(iv) by removing the word
``methods'' and by adding in its place the word ``procedures''; in the
last sentence of paragraph (e)(1) introductory text and in the first
sentence of paragraph (e)(2)(i) by removing the word ``methods'' each
time it appears and by adding in its place the word ``procedures''; and
by revising the first two sentences of paragraphs (d)(1)(i) and
(d)(1)(ii)(a) to read as follows:
Sec. 314.50 Content and format of an application.
* * * * *
(d) * * *
(1) * * *
(i) Drug substance. A full description of the drug substance
including its physical and chemical characteristics and stability; the
name and address of its manufacturer; the method of synthesis (or
isolation) and purification of the drug substance; the process controls
used during manufacture and packaging; and the specifications necessary
to ensure the identity, strength, quality, and purity of the drug
substance and the bioavailability of the drug products made from the
substance, including, for example, tests, analytical procedures, and
acceptance criteria relating to stability, sterility, particle size,
and crystalline form. The application may provide additionally for the
use of alternatives to meet any of these requirements, including
alternative sources, process controls, and analytical procedures. * * *
(ii)(a) Drug product. A list of all components used in the
manufacture of the drug product (regardless of whether they appear in
the drug product) and a statement of the composition of the drug
product; the specifications for each component; the name and address of
each manufacturer of the drug product; a description of the
manufacturing and packaging procedures and in-process controls for the
drug product; the specifications necessary to ensure the identity,
strength, quality, purity, potency, and bioavailability of the drug
product, including, for example, tests, analytical procedures, and
acceptance criteria relating to sterility, dissolution rate, containers
and closure systems; and stability data with proposed expiration
dating. The application may provide additionally for the use of
alternatives to meet any of these requirements, including alternative
components, manufacturing and packaging procedures, in-process
controls, and analytical procedures. * * *
* * * * *
Sec. 314.60 [Amended]
10. Section 314.60 Amendments to an unapproved application is
amended in paragraph (c) by removing the phrase ``, other than a
foreign applicant,''.
11. Section 314.70 is revised to read as follows:
Sec. 314.70 Supplements and other changes to an approved application.
(a) Changes to an approved application. (1) The applicant shall
notify FDA about each change in each condition established in an
approved application beyond the variations already provided for in the
application. The notice is required to describe the change fully.
Depending on the type of change, the applicant shall notify FDA about
it in a supplement under paragraph (b) or (c) of this section or by
inclusion of the information in the annual report to the application
under paragraph (d) of this section.
(2) The holder of an approved application under section 505 of the
act shall validate the effects of the change on the identity, strength,
quality, purity, or potency of the drug as these factors may relate to
the safety or effectiveness of the drug before distributing a drug made
with a manufacturing change.
(3) Notwithstanding the requirements of paragraphs (b) and (c) of
this section, an applicant shall make a change provided for in those
paragraphs in accordance with a regulation or guidance that provides
for a less burdensome notification of the change (for example, by
submission of a supplement that does not require approval prior to
distribution of the product or in an annual report).
(4) The applicant shall promptly revise all promotional labeling
and advertising to make it consistent with any labeling change
implemented in accordance with this section.
(5) Except for a supplement providing for a change in the labeling,
the applicant shall include in each supplemental application providing
for a change under paragraph (b) or (c) of this section a statement
certifying that a field copy of the supplement has been provided to the
applicant's home FDA district office.
(6) A supplement or annual report shall include in the cover letter
a list of all changes contained in the supplement or annual report.
(b) Changes requiring supplement submission and approval prior to
distribution of the product made using the change (major changes). (1)
A supplement shall be submitted for any change in the product,
production process, quality controls, equipment, or facilities that has
a substantial potential to have an adverse effect on the identity,
strength, quality, purity, or potency of the product as these factors
may relate to the safety or effectiveness of the product.
[[Page 34623]]
(2) These changes include, but are not limited to:
(i) Except as provided in paragraphs (c) and (d) of this section,
changes in the qualitative or quantitative formulation of the drug,
including inactive ingredients, or in the specifications provided in
the approved application;
(ii) Changes requiring completion of studies in accordance with
part 320 of this chapter to demonstrate the equivalence of the drug to
the drug as manufactured without the change or to the reference listed
drug;
(iii) Changes that may affect product sterility assurance, such as
changes in product or component sterilization method(s) or an addition,
deletion, or substitution of steps in an aseptic processing operation;
(iv) Changes in the synthesis or manufacture of the drug substance
that may affect the impurity profile and/or the physical, chemical, or
biological properties of the drug substance;
(v) Changes in labeling, except those described in paragraphs
(c)(6)(iii), (d)(2)(ix), or (d)(2)(x) of this section;
(vi) Changes in a container closure system that controls drug
delivery or that may affect the impurity profile of the drug product;
(vii) Changes solely affecting a natural product, a recombinant
DNA-derived protein/polypeptide product, or a complex or conjugate of a
drug with a monoclonal antibody for the following:
(A) Changes in the virus or adventitious agent removal or
inactivation method(s);
(B) Changes in the source material or cell line; and
(C) Establishment of a new master cell bank or seed.
(viii) Changes to a product under an application that is subject to
a validity assessment because of significant questions regarding the
integrity of the data supporting that application.
(3) The applicant must obtain approval of a supplement from FDA
prior to distribution of a product made using a change under paragraph
(b) of this section. Except for submissions under paragraph (e) of this
section, the following shall be contained in the supplement:
(i) A detailed description of the proposed change;
(ii) The product(s) involved;
(iii) The manufacturing site(s) or area(s) affected;
(iv) A description of the methods used and studies performed to
evaluate the effect of the change on the identity, strength, quality,
purity, or potency of the product as these factors may relate to the
safety or effectiveness of the product (validating the effects of the
change);
(v) The data derived from such studies;
(vi) For a natural product, a recombinant DNA-derived protein/
polypeptide product, or a complex or conjugate of a drug with a
monoclonal antibody, relevant validation protocols shall be provided in
addition to the requirements in paragraphs (b)(3)(iv) and (b)(3)(v) of
this section; and
(vii) For sterilization process and test methodologies, relevant
validation protocols shall be provided in addition to the requirements
in paragraphs (b)(3)(iv) and (b)(3)(v) of this section; and
(viii) A reference list of relevant standard operating procedures
(SOP's) when applicable.
(4) An applicant may ask FDA to expedite its review of a supplement
for public health reasons or if a delay in making the change described
in it would impose an extraordinary hardship on the applicant. Such a
supplement and its mailing cover should be plainly marked: ``Prior
Approval Supplement-Expedited Review Requested.''
(c) Changes requiring supplement submission at least 30 days prior
to distribution of the drug product made using the change (moderate
changes). (1) A supplement shall be submitted for any change in the
product, production process, quality controls, equipment, or facilities
that has a moderate potential to have an adverse effect on the
identity, strength, quality, purity, or potency of the product as these
factors may relate to the safety or effectiveness of the product. If
the change concerns labeling, include 12 copies of final printed
labeling.
(2) These changes include, but are not limited to:
(i) A change in the container closure system that does not affect
the quality of the final drug product; and
(ii) Changes solely affecting a natural protein product, a
recombinant DNA-derived protein/polypeptide product or a complex or
conjugate of a drug with a monoclonal antibody, including:
(A) An increase or decrease in production scale during finishing
steps that involves new or different equipment; and
(B) Replacement of equipment with that of similar, but not
identical, design and operating principle that does not affect the
process methodology or process operating parameters.
(3) A supplement submitted under paragraph (c)(1) of this section
is required to give a full explanation of the basis for the change and
identify the date on which the change is to be made. The supplement
shall be labeled ``Supplement--Changes Being Effected in 30 Days'' or,
if applicable under paragraph (c)(6) of this section, ``Supplement--
Changes Being Effected.''
(4) Pending approval of the supplement by FDA, except as provided
in paragraph (c)(6) of this section, distribution of the product made
using the change may begin not less than 30 days after receipt of the
supplement by FDA. The information listed in paragraphs (b)(3)(i)
through (b)(3)(viii) of this section shall be contained in the
supplement.
(5) The applicant shall not distribute the product made using the
change if within 30 days following FDA's receipt of the supplement, FDA
informs the applicant that either:
(i) The change requires approval prior to distribution of the
product in accordance with paragraph (b) of this section; or
(ii) Any of the information required under paragraph (c)(4) of this
section is missing; the applicant shall not distribute the product made
using the change until FDA determines that compliance with this section
is achieved.
(6) The agency may designate a category of changes for the purpose
of providing that, in the case of a change in such category, the holder
of an approved application may commence distribution of the drug
involved upon receipt by the agency of a supplement for the change.
These changes include, but are not limited to:
(i) Addition to a specification or changes in the methods or
controls to provide increased assurance that the drug will have the
characteristics of identity, strength, quality, purity, or potency that
it purports or is represented to possess;
(ii) A change in the size and/or shape of a container for a
nonsterile drug product, except for solid dosage forms, without a
change in the labeled amount of product or from one container closure
system to another;
(iii) Changes in the labeling to accomplish any of the following:
(A) To add or strengthen a contraindication, warning, precaution,
or adverse reaction;
(B) To add or strengthen a statement about drug abuse, dependence,
psychological effect, or overdosage;
(C) To add or strengthen an instruction about dosage and
administration that is intended to increase the safe use of the
product;
(D) To delete false, misleading, or unsupported indications for use
or claims for effectiveness; or
[[Page 34624]]
(E) Any other changes specifically requested by FDA.
(7) If the agency disapproves the supplemental application, it may
order the manufacturer to cease distribution of the drug products made
with the manufacturing change.
(d) Changes to be described in an annual report (minor changes).
(1) Changes in the product, production process, quality controls,
equipment, or facilities that have a minimal potential to have an
adverse effect on the identity, strength, quality, purity, or potency
of the product as these factors may relate to the safety or
effectiveness of the product shall be documented by the applicant in
the next annual report in accordance with Sec. 314.81(b)(2).
(2) These changes include, but are not limited to:
(i) Any change made to comply with an official compendium that is
consistent with FDA requirements and provides increased assurance that
the drug will have the characteristics of identity, strength, quality,
purity, or potency that it purports or is represented to possess;
(ii) The deletion or reduction of an ingredient intended to affect
only the color of the product;
(iii) Replacement of equipment with that of the same design and
operating principles except for equipment used with a natural protein
product, a recombinant DNA-derived protein/polypeptide product, or a
complex or conjugate of a drug with a monoclonal antibody;
(iv) A change in the size and/or shape of a container containing
the same number of dosage units for a nonsterile solid dosage form,
without a change from one container closure system to another;
(v) A change within the container closure system for a nonsterile
drug product, based upon a showing of equivalency to the approved
system under a protocol approved in the application or published in an
official compendium;
(vi) An extension of an expiration dating period based upon full
shelf life data on full production batches obtained from a protocol
approved in the application;
(vii) The addition, deletion, or revision of an alternate
analytical procedure that provides the same or increased assurance of
the identity, strength, quality, purity, or potency of the material
being tested as the analytical procedure described in the approved
application;
(viii) The addition by embossing, debossing, or engraving of a code
imprint to a solid oral dosage form drug product other than a modified
release dosage form, or a minor change in an existing code imprint;
(ix) A change in the labeling concerning the description of the
drug product or in the information about how the drug is supplied, that
does not involve a change in the dosage strength or dosage form; and
(x) An editorial or similar minor change in labeling.
(3) For changes under this category, the applicant is required to
submit in the annual report a list of all products involved; and
(i) A statement by the holder of the approved application that the
effects of the change have been validated;
(ii) A full description of the manufacturing and controls changes,
including the manufacturing site(s) or area(s) involved; and
(iii) The date each change was made, a cross-reference to relevant
validation protocols and/or SOP's, and relevant data from studies and
tests performed to evaluate the effect of the change on the identity,
strength, quality, purity, or potency of the product as these factors
may relate to the safety or effectiveness of the product (validation).
(e) Protocols. An applicant may submit one or more protocols
describing the specific tests and validation studies and acceptable
limits to be achieved to demonstrate the lack of adverse effect for
specified types of manufacturing changes on the identity, strength,
quality, purity, or potency of the drug as these factors may relate to
the safety or effectiveness of the drug. Any such protocols, or changes
to a protocol, shall be submitted as a supplement requiring approval
from FDA prior to distribution of a drug produced with the
manufacturing change. The supplement, if approved, may subsequently
justify a reduced reporting category for the particular change because
the use of the protocol for that type of change reduces the potential
risk of an adverse effect.
(f) Patent information. The applicant shall comply with the patent
information requirements under section 505(c)(2) of the act.
(g) Claimed exclusivity. If an applicant claims exclusivity under
Sec. 314.108 upon approval of a supplement for change to its previously
approved drug product, the applicant shall include with its supplement
the information required under Sec. 314.50(j).
Sec. 314.81 [Amended]
12. Section 314.81 Other postmarketing reports is amended in
paragraph (b)(1)(ii) by removing the word ``specifications'' and by
adding in its place the word ``specification''.
Sec. 314.94 [Amended]
13. Section 314.94 Content and format of an abbreviated application
is amended in the second sentence of paragraph (d)(2) by removing the
word ``methods'' each time it appears and by adding in its place the
word ``procedures''.
Sec. 314.410 [Amended]
14. Section 314.410 Imports and exports of new drugs is amended in
paragraph (b)(2) by removing the word ``specifications'' and by adding
in its place the word ``specification''.
Sec. 314.430 [Amended]
15. Section 314.430 Availability for public disclosure of data and
information in an application or abbreviated application is amended in
paragraph (e)(6) by removing the word ``method'' and by adding in its
place the word ``procedure''.
PART 600--BIOLOGICAL PRODUCTS: GENERAL
16. The authority citation for 21 CFR part 600 is revised to read
as follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 356a, 360, 360i,
371, 374; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.
17. Section 600.3 is amended by adding paragraphs (hh) and (ii) to
read as follows:
Sec. 600.3 Definitions.
* * * * *
(hh) Specification, as used in Sec. 601.12 of this chapter, means
the quality standard (i.e., tests, analytical procedures, and
acceptance criteria) provided in an approved application to confirm the
quality of drug substances, drug products, intermediates, raw
materials, reagents, and other components including container closure
systems, and in-process materials. For the purpose of this definition,
acceptance criteria means numerical limits, ranges, or other criteria
for the tests described.
(ii) Validate the effects of the change, as used in Sec. 601.12 of
this chapter, means to assess the effect of a manufacturing change on
the identity, strength, quality, purity, or potency of a drug as these
factors relate to the safety or effectiveness of the drug.
PART 601--LICENSING
18. The authority citation for 21 CFR part 601 is revised to read
as follows:
Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353,
355, 356a, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216,
241, 262, 263.
[[Page 34625]]
19. Section 601.12 is amended by revising paragraphs (a),
(b)(2)(i), (d)(2)(i) through (d)(2)(v), and (d)(2)(vii); by adding
paragraph (b)(4), (c)(6), (d)(3)(iii), and (f)(2)(i)(E); and by
removing and reserving paragraph (c)(2)(i) to read as follows:
Sec. 601.12 Changes to an approved application.
(a) General. (1) As provided by this section, an applicant shall
inform the Food and Drug Administration (FDA) about each change in the
product, production process, quality controls, equipment, facilities,
responsible personnel, or labeling established in the approved license
application(s).
(2) Before distributing a product made using a change, an applicant
shall validate the effects of the change and demonstrate through
appropriate validation and/or other clinical and/or nonclinical
laboratory studies the lack of adverse effect of the change on the
identity, strength, quality, purity, or potency of the product as they
may relate to the safety or effectiveness of the product.
(3) Notwithstanding the requirements of paragraphs (b), (c), and
(f) of this section, an applicant shall make a change provided for in
those paragraphs in accordance with a regulation or guidance that
provides for a less burdensome notification of the change (for example,
by submission of a supplement that does not require approval prior to
distribution of the product or in an annual report).
(4) The applicant shall promptly revise all promotional labeling
and advertising to make it consistent with any labeling change
implemented in accordance with this section.
(5) A supplement or annual report shall include in the cover letter
a list of all changes contained in the supplement or annual report.
(b) * * *
(2) * * *
(i) Except as provided in paragraphs (c) and (d) of this section,
changes in the qualitative or quantitative formulation, including
inactive ingredients, or in the specifications provided in the approved
application;
* * * * *
(4) An applicant may ask FDA to expedite its review of a supplement
for public health reasons or if a delay in making the change described
in it would impose an extraordinary hardship on the applicant. Such a
supplement and its mailing cover should be plainly marked: ``Prior
Approval Supplement-Expedited Review Requested.''
(c) * * *
(2) * * *
(i) [Reserved]
* * * * *
(6) If the agency disapproves the supplemental application, it may
order the manufacturer to cease distribution of the products made with
the manufacturing change.
(d) * * *
(2) * * *
(i) Any change made to comply with an official compendium that is
consistent with FDA requirements and provides increased assurance that
the drug will have the characteristics of identity, strength, quality,
purity, or potency that it purports or is represented to possess;
(ii) The deletion or reduction of an ingredient intended only to
affect the color of the product, except that a change intended only to
affect Blood Grouping Reagents requires supplement submission and
approval prior to distribution of the product made using the change in
accordance with the requirements set forth in paragraph (b) of this
section;
(iii) An extension of an expiration dating period based upon full
shelf life data on full production batches obtained from a protocol
approved in the application;
(iv) A change within the container closure system for a nonsterile
drug product, based upon a showing of equivalency to the approved
system under a protocol approved in the application or published in an
official compendium;
(v) A change in the size and/or shape of a container containing the
same number of dosage units for a nonsterile solid dosage form, without
a change from one container closure system to another;
* * * * *
(vii) The addition, deletion, or revision of an alternate
analytical procedure that provides the same or increased assurance of
the identity, strength, quality, purity, or potency of the material
being tested as the analytical procedure described in the approved
application.
(3) * * *
(iii) A statement by the holder of the approved application or
license that the effects of the change have been validated.
* * * * *
(f) * * *
(2) * * *
(i) * * *
(E) Any other changes specifically requested by FDA.
* * * * *
Dated: June 18, 1999.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 99-16191 Filed 6-25-99; 8:45 am]
BILLING CODE 4160-01-F
